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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive HP:0000007

All reported probands carry biallelic DNAJC3 variants - most often a homozygous nonsense, frameshift or whole-gene deletion allele in a consanguineous pedigree, but compound heterozygosity has also been described. Heterozygous carriers in the reported families are unaffected. Consanguinity is frequent but not required - the German proband reported in 2024 had non-consanguineous parents. Penetrance of the multisystem phenotype appears high among individuals with severe biallelic loss-of-function alleles, but it is age-dependent and has never been formally quantified, so it is recorded as UNKNOWN rather than COMPLETE: the adult homozygote in PMID:42353846 had no clinically evident neurological disease at evaluation, and the sibling pair in PMID:34630333 differed in both ataxia severity and brain MRI at comparable ages. Expressivity is unambiguously variable.

Autosomal recessive inheritance Penetrance: UNKNOWN Expressivity: VARIABLE

Show evidence (2 references)

PMID:25466870 SUPPORT Human Clinical

"Our findings demonstrate that loss-of-function DNAJC3 mutations lead to a monogenic, recessive form of diabetes mellitus in humans."

States the recessive mode of inheritance for loss-of-function DNAJC3 alleles.

PMID:33486469 SUPPORT Human Clinical

"They were heterozygous compound and homozygous for novel loss-of-function mutations in DNAJC3."

Documents both compound heterozygous and homozygous biallelic genotypes in unrelated probands.

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Discussions and Knowledge Gaps

2

Why does loss of a ubiquitously expressed ER co-chaperone kill cerebellar, corticospinal, peripheral and auditory neurons, and is that neuronal death mechanistically the same event as the beta-cell death?

KNOWLEDGE GAP OPEN gap_dnajc3_neuronal_death_mechanism

Attached to

pathophysiology#Progressive Central and Peripheral Neurodegeneration pathophysiology#Disturbed Lipid Homeostasis and Mitochondrial Dysfunction

The beta-cell arm is mechanistically solved to the level of effector proteins: DNAJC3 loss causes BIM/PUMA-dependent mitochondrial apoptosis, shown in rodent and human beta cells and matched by the knockout mouse. The neurological arm has no equivalent. The only mechanistic data are from patient fibroblasts (lipid accumulation, mitochondrial dysfunction, amyloid precursor protein handling) and from a retinal ganglion cell phenotype in the knockout mouse. Neither addresses cerebellum, corticospinal tract, peripheral nerve or cochlea, and the knockout mouse is reported for diabetes rather than for generalised neurodegeneration. Until this is closed, the entry deliberately does not assert that the neurodegeneration is a downstream consequence of the diabetes, nor that it shares the BIM/PUMA effector mechanism.

Proposed experiments

Neuronal-lineage differentiation of patient iPSC

exp_dnajc3_patient_ipsc_neurons

Differentiate patient-derived and isogenic-corrected iPSC into cerebellar, motor and sensory neuronal lineages and test whether the BIM/PUMA mitochondrial apoptosis route observed in beta cells operates, or whether the lipid/mitochondrial route observed in fibroblasts dominates.

Neuropathological characterisation of the Dnajc3-null mouse

exp_dnajc3_null_mouse_neuropathology

Systematically phenotype cerebellum, corticospinal tract, peripheral nerve and cochlea in aged Dnajc3 knockout mice, which have been studied for diabetes and retina but not for the full human neurological spectrum.

What explains the wide phenotypic variability, including an adult homozygous for a nonsense allele with no clinically evident neurological disease?

KNOWLEDGE GAP OPEN gap_dnajc3_phenotypic_variability

Attached to

pathophysiology#Biallelic DNAJC3 Loss-of-Function Variants

Reported genotypes are overwhelmingly null, yet outcomes differ sharply. One sibling pair sharing a variant differed in both ataxia severity and brain MRI; a 34-year-old homozygous for p.Arg393* had diabetes, deafness, hypothyroidism and short stature but no clinically evident neurological signs at evaluation. Since allelic severity cannot easily explain differences between carriers of the same allele, modifiers, ascertainment or the sensitivity of clinical examination must be doing the work, and none has been investigated. This matters practically, because it determines whether a newly diagnosed child should be counselled to expect neurodegeneration.

Proposed experiments

Systematic neurological phenotyping of a DNAJC3 cohort

exp_dnajc3_cohort_neurophenotyping

Apply uniform neurological examination, nerve conduction studies, audiometry and brain MRI to all reported and newly identified DNAJC3-deficient individuals, to establish whether apparently unaffected adults are truly spared or only subclinically affected.

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Pathophysiology

9

Biallelic DNAJC3 Loss-of-Function Variants

Homozygous or compound heterozygous nonsense, frameshift or whole-gene deletion variants in DNAJC3 abolish the protein. Reported alleles include a homozygous stop mutation and a homozygous whole-gene deletion in the two index families, and later nonsense (p.Arg393*), frameshift and missense (p.Arg415Pro) alleles. The absence of the protein - not a retained or aggregated mutant - is the primary lesion, which is why this entry models a chaperone-capacity failure rather than an ER storage disease.

DNAJC3 hgnc:9439

Genetic context DNAJC3 hgnc:9439 variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Biallelic null or severely hypomorphic alleles; heterozygotes are unaffected. Compound heterozygosity is also reported, so the HOMOZYGOUS value records the commonest reported state rather than an obligatory one.

Downstream

Loss of p58IPK Co-Chaperone Function in the Endoplasmic Reticulum Loss-of-function alleles result in complete absence of the DNAJC3 protein product in patient cells.

Show evidence (3 references)

PMID:25466870 SUPPORT Human Clinical

"Exome sequencing identified a homozygous stop mutation in DNAJC3."

Identifies the founding genotype in the index sibship.

PMID:42353846 SUPPORT Human Clinical

"Genetic analysis using whole-exome sequencing identified a homozygous likely pathogenic DNAJC3 variant, c.1177C>T p.(Arg393*), confirming the diagnosis of DNAJC3-related syndromic monogenic diabetes."

A further homozygous nonsense allele, showing the recurrent truncating mutational mechanism.

PMID:40534546 SUPPORT Human Clinical

"Exome sequencing and CNV (Copy Number Variation) analysis revealed a novel homozygous c.1244G>C (p.Arg415Pro) variant in DNAJC3 gene."

Shows that missense as well as truncating alleles are reported, broadening the mutational spectrum.

Loss of p58IPK Co-Chaperone Function in the Endoplasmic Reticulum

p58IPK is an ER-lumenal DnaJ/Hsp40 co-chaperone of BiP and, in parallel, an inhibitor of the eIF2-alpha kinases PERK and PKR that acts as the negative feedback limb terminating the translational-attenuation phase of the unfolded protein response. Its loss therefore removes two things at once: productive BiP-assisted folding of nascent secretory clients, and the brake that returns the UPR to baseline. In pancreatic beta cells BiP has been shown to require p58IPK for productive proinsulin folding specifically.

protein folding GO:0006457 ↓ DECREASED

BiP (HSPA5) co-chaperone binding GO:0051087 ⇓ LOSS OF FUNCTION

Downstream

Dysregulated Unfolded Protein Response and Chronic ER Stress Without the p58IPK feedback limb, eIF2-alpha kinase signalling through PERK is no longer restrained and ER stress signalling becomes chronic rather than self-limiting.

Disrupted Sec61 Translocon Gating and ER Calcium Leak BiP closes the Sec61 polypeptide-conducting channel with the help of its lumenal co-chaperones ERj3 and ERj6 (p58IPK/DNAJC3); depleting ERj6 phenocopies BiP depletion and increases ER calcium leakage.

Show evidence (3 references)

PMID:33486469 SUPPORT Human Clinical

"DNAJC3, also known as P58IPK, is an Hsp40 family member that interacts with and inhibits PKR-like ER-localized eIF2α kinase (PERK)."

States the PERK-inhibitory molecular function that is lost.

PMID:25329545 SUPPORT In Vitro

"However, we show that p58IPK is a general inhibitor of the eIF2α kinases in that it also interacts with GCN2."

Extends the inhibitory role of p58IPK beyond PERK to the wider eIF2-alpha kinase family, so its loss disinhibits translational attenuation broadly.

PMID:42224595 SUPPORT Model Organism

"BiP requires p58IPK for productive proinsulin folding, whereas nonstoichiometric BiP excess actually hinders proinsulin folding."

Shows the BiP-p58IPK partnership is specifically required for folding the beta cell's dominant secretory client, explaining beta-cell vulnerability.

Dysregulated Unfolded Protein Response and Chronic ER Stress

In the absence of its feedback inhibitor, PERK-mediated UPR signalling runs unopposed and cells sit in a state of chronic, unresolved ER stress and are sensitised to any further folding load. DNAJC3 disease is grouped with the other monogenic diabetes syndromes that act through the PERK arm of the ER stress response.

PERK-mediated unfolded protein response GO:0036499 ↑ INCREASED response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED

Downstream

Pancreatic Beta-Cell Apoptosis via BIM and PUMA Chronic ER stress in a cell with an extreme secretory load converts an adaptive response into a death signal.

Disturbed Lipid Homeostasis and Mitochondrial Dysfunction Patient fibroblasts accumulate lipid, show increased sensitivity to cholesterol stress, and activate the UPR, with downstream alteration of ER-Golgi trafficking and mitochondrial function.

Show evidence (2 references)

PMID:33486469 SUPPORT Human Clinical

"This report confirms previously described features and expands the clinical spectrum of syndromic DNAJC3 diabetes, one of the five monogenic forms of diabetes pertaining to the PERK pathway of the endoplasmic reticulum stress response."

Places the disorder mechanistically within the PERK arm of the ER stress response.

PMID:42353846 SUPPORT Other

"Because of their extensive insulin biosynthesis requirements, pancreatic β-cells are highly susceptible to ER stress. Loss of the co-chaperone activity of DNAJC3 leads to chronic ER stress, subsequent loss of β-cell functionality and ultimately insulin deficiency"

Review statement of the chronic-ER-stress-to-insulin-deficiency chain and of why beta cells are the exposed tissue.

Disrupted Sec61 Translocon Gating and ER Calcium Leak

The proposed explanation for the early hyperinsulinaemic phase of the syndrome. p58IPK, working with BiP, assists closure of the Sec61 polypeptide-conducting channel; without it, calcium leaks from the ER lumen into the cytosol of the beta cell and inappropriately drives insulin exocytosis. This is offered by its authors as the most likely mechanism rather than a demonstrated one, and is curated here as such.

pancreatic beta cell CL:0000169

intracellular calcium ion homeostasis GO:0006874 ↓ DECREASED

Downstream

Hyperinsulinaemic Hypoglycaemia of Infancy and Childhood Cytosolic calcium rise from an ER leak is proposed to drive unregulated insulin release before beta-cell mass is lost.

Show evidence (1 reference)

PMID:38279270 SUPPORT Human Clinical

"This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis."

Frames the calcium-homeostasis route as the distinguishing feature of DNAJC3-related hyperinsulinism.

Hyperinsulinaemic Hypoglycaemia of Infancy and Childhood

The first, and easily missed, endocrine phase. Affected infants and young children can present with diazoxide-responsive hyperinsulinaemic hypoglycaemia, described around two years of age in one series and persisting into adolescence in another individual, before the beta-cell mass declines and the phenotype inverts to insulin deficiency.

Animal models

Dnajc3 (P58IPK) knockout mouse Mouse partially recapitulates Young knockout mice show increased insulin release per cell during high-glucose stimulation, the cellular direction predicted by the human hyperinsulinaemic phase.

Downstream

Insulin Deficiency and Pancreatic Atrophy The same beta cells that oversecrete early are progressively lost, so the hyperinsulinaemic phase gives way to insulin deficiency in the second decade.

Show evidence (2 references)

PMID:34654017 SUPPORT Human Clinical

"This report confirms DNAJC3 as a cause of syndromic congenital hyperinsulinaemic hypoglycaemia."

Independent confirmation that hyperinsulinaemic hypoglycaemia belongs to the DNAJC3 phenotype.

PMID:38279270 SUPPORT Human Clinical

"The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence."

Shows the hyperinsulinaemic phase can be the dominant and persisting presentation rather than a transient neonatal finding.

Pancreatic Beta-Cell Apoptosis via BIM and PUMA

The measured consequence of DNAJC3 loss in beta cells is death, not secretory failure. Silencing DNAJC3 in INS-1E cells, primary rat beta cells, human islets and iPSC-derived beta cells left insulin content and secretion intact but triggered apoptosis through the mitochondrial pathway, engaged by the BH3-only proteins BIM and PUMA. The Dnajc3-null mouse shows the corresponding in vivo phenotype: progressive islet-cell apoptosis with preserved function in the beta cells that remain.

pancreatic beta cell CL:0000169

intrinsic apoptotic signaling pathway GO:0097193 ↑ INCREASED

Experimental models

DNAJC3-silenced human islets and iPSC-derived beta cells CELL LINE Directly reproduces the beta-cell death mechanism, in human as well as rodent cells, and identifies its molecular effectors.

Animal models

Dnajc3 (P58IPK) knockout mouse Mouse partially recapitulates Reproduces the progressive islet-cell apoptosis and consequent hyperglycaemia with preserved function in surviving beta cells.

Downstream

Insulin Deficiency and Pancreatic Atrophy Cumulative loss of beta-cell mass produces absolute insulin deficiency.

Show evidence (3 references)

PMID:33486469 SUPPORT In Vitro

"DNAJC3 silencing did not impair insulin content or secretion."

A negative result that is load-bearing here - it excludes a primary secretory defect and points to cell loss as the mechanism.

PMID:15793246 SUPPORT Model Organism

"we generated deletion mutant mice that showed a gradual onset of glucosuria and hyperglycemia associated with increasing apoptosis of pancreatic islet cells"

In vivo confirmation that loss of p58IPK causes progressive islet-cell apoptosis and hyperglycaemia.

PMID:15793246 SUPPORT Model Organism

"Lack of P58(IPK) had no apparent effect on the functional integrity of viable beta-cells."

Independent in vivo agreement with the in vitro finding that surviving beta cells function normally.

Insulin Deficiency and Pancreatic Atrophy

Progressive beta-cell loss produces non-autoimmune, insulin-requiring diabetes mellitus, characteristically in the second decade. Pancreatic imaging in at least one reported family showed a small, atrophic pancreas, suggesting the structural counterpart of the cellular loss. No edge is drawn from this node to the neurodegeneration: the neurological arm frequently precedes the diabetes diagnosis and is not modelled here as a diabetic complication but as a parallel consequence of the same upstream chaperone-capacity failure.

Show evidence (2 references)

PMID:34630333 SUPPORT Human Clinical

"Patients with DNAJC3 mutations may possess a small atrophic pancreas."

Reports the pancreatic structural finding accompanying the insulin deficiency.

PMID:34630333 SUPPORT Human Clinical

"Tests for markers of autoimmune diabetes were negative."

Establishes the non-autoimmune character of the diabetes in a molecularly confirmed patient.

Disturbed Lipid Homeostasis and Mitochondrial Dysfunction

Unbiased proteomics of DNAJC3-deficient patient fibroblasts identified perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function and amyloid precursor protein processing. This is the best current candidate bridge from an ER co-chaperone defect to neuronal vulnerability, but it rests on fibroblast data rather than on neural tissue, and the entry treats it as a proposed rather than an established link.

response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED

Experimental models

DNAJC3-deficient patient fibroblasts PRIMARY CELL CULTURE Provides the proteomic and functional measurements behind this node.

Downstream

Progressive Central and Peripheral Neurodegeneration Impaired oxidative phosphorylation and lipid handling are proposed to underlie the loss of long-lived, high-demand neurons.

Show evidence (1 reference)

PMID:34692675 SUPPORT In Vitro

"In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the DNAJC3 pathophysiology."

States mitochondrial dysfunction as a major contributor to the disease mechanism.

Progressive Central and Peripheral Neurodegeneration

A slowly progressive, generalised neurodegeneration affecting cerebellum, corticospinal tracts, peripheral nerve and the auditory system, with cerebral atrophy on MRI. Sensorineural hearing loss is frequently the earliest neurological sign, appearing around five to six years of age, well before the diabetes. Severity is highly variable between and within families.

neuron CL:0000540

neuron apoptotic process GO:0051402 ↑ INCREASED

Animal models

p58IPK knockout mouse retina Mouse partially recapitulates Demonstrates that neurons lacking p58IPK die under ER stress, providing a cell-type-specific in vivo instance of the neurodegenerative arm.

Show evidence (2 references)

PMID:25466870 SUPPORT Human Clinical

"We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy."

The defining clinical description of the neurological arm in the index sibship.

PMID:32738013 SUPPORT Human Clinical

"Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life."

Establishes the age of onset and the sequence in which the neurological features appear.

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Pathograph

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Phenotypes

16

Ear 1

Sensorineural Hearing Loss Sensorineural hearing impairment HP:0000407

Show evidence (2 references)

PMID:40534546 SUPPORT Human Clinical

"Sensorineural hearing loss developed 5 months after the diagnosis of diabetes and intellectual functions were impaired."

Documents sensorineural hearing loss in a molecularly confirmed patient and shows it can follow rather than precede the diabetes.

PMID:32738013 SUPPORT Human Clinical

"Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life."

Gives the early childhood age of onset of the deafness.

Endocrine 2

Juvenile-Onset Non-Autoimmune Diabetes Mellitus HP:0000819

Show evidence (2 references)

PMID:42353846 SUPPORT Human Clinical

"DNAJC3-related syndromic monogenic diabetes is a rare autosomal recessive disorder that presents as juvenile-onset non-autoimmune diabetes; it has been associated with sensorineural hearing loss, hypothyroidism, short stature, and variable degrees of neurological manifestations."

Characterises the diabetes as juvenile-onset and non-autoimmune and lists the associated features.

PMID:40534546 SUPPORT Human Clinical

"Loss-of-function mutations in DNAJC3 lead to early-onset diabetes and multisystemic neurodegeneration."

Confirms early-onset diabetes as a core feature of the DNAJC3 phenotype.

Hypothyroidism HP:0000821

Show evidence (1 reference)

PMID:28940199 SUPPORT Human Clinical

"Hypothyroidism is a newly identified feature in addition to the known phenotype (diabetes with multisystemic neurodegeneration)."

The report that added hypothyroidism to the recognised DNAJC3 phenotype.

Eye 1

Retinal Dystrophy HP:0000556

Show evidence (2 references)

PMID:38279270 SUPPORT Other

"biallelic DNAJC3 variants have been linked to multisystem neurodegeneration with ataxia, peripheral neuropathy, cognitive impairment, sensorineural hearing loss, and retinal dystrophy as well as short stature, hypothyroidism, facial dysmorphism, mild skeletal bone deformities, and early-onset..."

Review summary listing retinal dystrophy among the reported features. Tagged OTHER because it is a literature summary in an introduction rather than a primary observation in that paper.

PMID:25655802 SUPPORT Model Organism

"Mice lacking p58(IPK) exhibited increased CHOP expression and loss of RGCs with aging (8-10 months)."

Provides the model-organism correlate for retinal vulnerability to p58IPK loss.

Head and Neck 2

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:33486469 SUPPORT Human Clinical

"The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities."

Lists microcephaly among the features of two unrelated molecularly confirmed patients.

Facial Dysmorphism Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:33486469 SUPPORT Human Clinical

"The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities."

Records facial dysmorphism as part of the reported phenotype.

Nervous System 6

Cerebellar and Gait Ataxia HP:0001251

Course: PROGRESSIVE

Show evidence (2 references)

PMID:34630333 SUPPORT Human Clinical

"At age 9 years, he developed an ataxic gait. Brain magnetic resonance imaging (MRI) revealed neurodegeneration."

Dates the onset of ataxia and links it to imaging evidence of neurodegeneration.

PMID:34654017 SUPPORT Human Clinical

"The full phenotype included neurodegeneration, ataxia, deafness, neuropathy, adolescent-onset diabetes mellitus, growth hormone deficiency and hypothyroidism."

Lists ataxia among the core features of the syndrome.

Peripheral Neuropathy HP:0009830

Show evidence (1 reference)

PMID:25466870 SUPPORT Human Clinical

"We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy."

Lists peripheral neuropathy among the defining features of the index sibship.

Demyelinating Features on Nerve Conduction Studies Demyelinating peripheral neuropathy HP:0007108

Show evidence (1 reference)

PMID:38279270 SUPPORT Human Clinical

"At 9.6 years of age, nerve conduction studies were consistent with mild sensorimotor demyelinating peripheral neuropathy, both of which are known features of a DNAJC3 loss of function"

The electrophysiological finding that characterises the neuropathy as demyelinating in that patient.

Cerebral White Matter Abnormality Abnormal cerebral white matter morphology HP:0002500

Show evidence (2 references)

PMID:34630333 SUPPORT Human Clinical

"Brain and spine MRI demonstrated bilateral subcortical white matter intensity with bilateral middle cerebellar peduncle involvement."

Reports the white matter and cerebellar peduncle imaging abnormality.

PMID:38279270 SUPPORT Human Clinical

"cranial MRI, were unremarkable, except for two small, nonspecific, patchy hyperintense frontal white matter lesions"

Shows the milder end of the imaging spectrum - explicitly nonspecific lesions on an otherwise unremarkable scan.

Cerebral Atrophy HP:0002059

Show evidence (2 references)

PMID:25466870 SUPPORT Human Clinical

"We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy."

Records cerebral atrophy in the index sibship.

PMID:34630333 SUPPORT Human Clinical

"His elder brother, who had the same mutation, had a similar history, except that he had milder ataxia and normal brain MRI finding at the age of 28 years."

Qualifies the finding - imaging can be normal in an adult carrying the same genotype, so cerebral atrophy is not obligate.

Cognitive Impairment HP:0100543

Show evidence (1 reference)

PMID:40534546 SUPPORT Human Clinical

"Sensorineural hearing loss developed 5 months after the diagnosis of diabetes and intellectual functions were impaired."

Documents impaired intellectual function in a molecularly confirmed patient.

Growth 1

Short Stature With Growth Hormone Deficiency HP:0004322

Show evidence (1 reference)

PMID:32738013 SUPPORT Human Clinical

"Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin."

Documents severe growth failure attributed to growth hormone deficiency.

Other 3

Hyperinsulinaemic Hypoglycaemia Hyperinsulinemic hypoglycemia HP:0000825

Temporal: TRANSIENT

Show evidence (2 references)

PMID:38279270 SUPPORT Human Clinical

"This individual has a markedly different clinical course, with diazoxide-responsive hyperinsulinemic hypoglycemia persisting through adolescence as a dominant feature of the syndrome, marked short stature, and only subtle neurological abnormalities."

Documents diazoxide responsiveness and persistence of the hyperinsulinaemic phase.

PMID:34654017 SUPPORT Human Clinical

"A subsequent report of two unrelated individuals extended the phenotype to include early-onset hyperinsulinaemic hypoglycaemia."

Records the addition of hyperinsulinaemic hypoglycaemia to the recognised phenotype.

Upper Motor Neuron Dysfunction HP:0002493

Show evidence (1 reference)

PMID:25466870 SUPPORT Human Clinical

"We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy."

Documents upper motor neuron damage as part of the core neurological phenotype.

Pancreatic Atrophy Abnormality of the pancreas HP:0001732

Show evidence (1 reference)

PMID:34630333 SUPPORT Human Clinical

"Patients with DNAJC3 mutations may possess a small atrophic pancreas."

Reports pancreatic atrophy as a structural feature of the disorder.

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Genetic Associations

1

DNAJC3

Gene: DNAJC3 hgnc:9439 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:25466870 SUPPORT Human Clinical

"Screening of a diabetes database with 226,194 individuals yielded eight phenotypically similar individuals and one family carrying a homozygous DNAJC3 deletion."

Independent replication of the gene-disease relationship in a second family from a large diabetes cohort.

PMID:25466870 SUPPORT Human Clinical

"This analysis revealed only one further loss-of-function allele in DNAJC3 and no further associations in subjects with only a subset of the features of the main phenotype."

Establishes the rarity of DNAJC3 loss-of-function alleles and, importantly, that partial phenotypes were not associated with the gene - which is why this entry treats the full syndrome, not its components, as the entity.

PMID:29767246 SUPPORT Human Clinical

"Genotyping of these variants revealed that DnaJ homolog subfamily C member 3 (DNAJC3) p.H238N segregated with diabetes in the family."

Cited to draw the boundary - a monoallelic DNAJC3 missense allele proposed for non-syndromic dominant type 2 diabetes, which is a different assertion from the recessive syndromic disorder curated here.

Variants (5)

Homozygous nonsense alleles Pathogenic

Gene: DNAJC3 hgnc:9439 nonsense

The commonest reported class. p.Arg194* was the founding allele in the index sibship and is the variant carried by one of the two patient fibroblast lines used for the proteomic work; p.Arg393* was reported in a Saudi adult. Both are predicted to truncate the protein before the C-terminal J domain, and the index alleles produce no detectable protein in patient fibroblasts.

Show evidence (2 references)

PMID:34692675 SUPPORT In Vitro

"We studied two fibroblast lines carrying a homozygous c.580C > T (NM_006260.4, p.Arg194∗) premature stop mutation in DNAJC3"

Gives the exact founding nonsense allele at cDNA and protein level.

PMID:42353846 SUPPORT Human Clinical

"Genetic analysis using whole-exome sequencing identified a homozygous likely pathogenic DNAJC3 variant, c.1177C>T p.(Arg393*), confirming the diagnosis of DNAJC3-related syndromic monogenic diabetes."

A second, independent homozygous nonsense allele.

Frameshift alleles Pathogenic

Gene: DNAJC3 hgnc:9439 frameshift

Two distinct frameshift alleles are reported: p.Trp186Glyfs*14, found in trans with a splice-acceptor variant, and a deletion in the final exon producing p.Lys456SerfsTer85, which elongates rather than truncates the protein and is predicted to abrogate the J domain. The latter is instructive because a last-exon frameshift escapes nonsense-mediated decay, so the mechanism is a non-functional J domain rather than absent message.

Show evidence (1 reference)

PMID:34654017 SUPPORT Human Clinical

"Here, we describe two siblings that recapitulate this extended phenotype in association with a homozygous novel mutation in the final exon of DNAJC3"

Reports the last-exon frameshift allele in a sibling pair.

Splice-acceptor allele in compound heterozygosity Pathogenic

Gene: DNAJC3 hgnc:9439 splice acceptor

A c.83-2A>G acceptor-site variant reported in trans with a frameshift allele in an individual whose dominant feature was diazoxide-responsive hyperinsulinaemic hypoglycaemia. Both were classified pathogenic by ACMG criteria. This allele class matters for test selection because splice-site variants outside the coding sequence are missed by some targeted assays.

Show evidence (1 reference)

PMID:38279270 SUPPORT Human Clinical

"The first variant is predicted to result in the loss of an acceptor splice site, while the second variant causes a frameshift resulting in a premature stop codon that halts protein synthesis."

Establishes the splice-acceptor plus frameshift compound-heterozygous genotype and its ACMG-pathogenic classification.

Multi-exon copy-number deletion spanning DNAJC3 Pathogenic

Gene: DNAJC3 hgnc:9439 copy number deletion

A homozygous deletion of about 72 kb removing DNAJC3 - and, in the family characterised in detail, the adjacent UGGT2 gene - was the second independent genotype found in the founding report. This is the allele class with the clearest practical consequence: a sequencing-only assay with no copy-number analysis will not detect it, so CNV analysis belongs in any diagnostic strategy for this disorder. The authors of the proteomic study note the UGGT2 involvement as a potential confounder but observe that all DNAJC3 patients present with very similar phenotypes.

Show evidence (2 references)

PMID:25466870 SUPPORT Human Clinical

"Screening of a diabetes database with 226,194 individuals yielded eight phenotypically similar individuals and one family carrying a homozygous DNAJC3 deletion."

Reports the whole-gene deletion genotype in an independent family.

PMID:34692675 SUPPORT In Vitro

"one line having a large homozygous deletion of 72 kb spanning DNAJC3 (and the adjacent UGGT2 gene), and control fibroblasts from three healthy donors, age and sex matched"

Gives the size of the deletion and names the adjacent gene it also removes.

Missense alleles Likely Pathogenic

Gene: DNAJC3 hgnc:9439 missense

Rarer than the truncating classes. A homozygous p.Arg415Pro variant was reported in a girl presenting in diabetic ketoacidosis, and p.His238Asn is the separately proposed monoallelic dominant type 2 diabetes allele that this entry excludes from the recessive syndrome. Missense alleles are the class for which functional interpretation is least secure, since the established disease mechanism is absence of protein.

Show evidence (1 reference)

PMID:40534546 SUPPORT Human Clinical

"Exome sequencing and CNV (Copy Number Variation) analysis revealed a novel homozygous c.1244G>C (p.Arg415Pro) variant in DNAJC3 gene."

Reports the homozygous missense allele and the assay that found it.

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Medical Actions

7

Insulin Replacement Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: insulin CHEBI:145810

Once the insulin-deficient phase is established, treatment is insulin. The diabetes is not autoimmune and is not insulin-resistant, but lifestyle measures and oral agents have proved insufficient in reported patients, who ultimately required insulin.

Show evidence (1 reference)

PMID:34630333 SUPPORT Human Clinical

"Lifestyle modification was introduced, but insulin therapy was eventually required."

Documents that insulin therapy became necessary despite initial conservative management.

Diazoxide for Hyperinsulinaemic Hypoglycaemia

Action: Pharmacotherapy NCIT:C15986

Agent: diazoxide CHEBI:4495

In the hyperinsulinaemic phase, hypoglycaemia has been reported to respond to diazoxide. This is phase-specific: the same patient will later need insulin, so the treatment target inverts over the course of the disease.

Mechanism Target:

INHIBITS Hyperinsulinaemic Hypoglycaemia of Infancy and Childhood — Diazoxide opens the beta-cell KATP channel and suppresses insulin release, addressing the hyperinsulinaemic phase symptomatically rather than correcting the underlying ER calcium leak.

Show evidence (1 reference)

PMID:38279270 SUPPORT Human Clinical

"This individual has a markedly different clinical course, with diazoxide-responsive hyperinsulinemic hypoglycemia persisting through adolescence as a dominant feature of the syndrome, marked short stature, and only subtle neurological abnormalities."

Documents diazoxide responsiveness of the hyperinsulinaemic hypoglycaemia in a DNAJC3-deficient patient.

Show evidence (1 reference)

PMID:38279270 SUPPORT Human Clinical

"Clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism."

Supports active screening for the treatable hyperinsulinaemic phase.

Metformin and Lifestyle Measures (Transitional Only)

Action: Pharmacotherapy NCIT:C15986

Agent: metformin CHEBI:6801

Reported in the early, mildly hyperglycaemic window before insulin becomes necessary. The published experience is that it buys time rather than controlling the disease: in one sibling, metformin plus lifestyle modification was started when diabetes appeared at 14 and insulin was required within a year as glycaemic control deteriorated. It should not be treated as an alternative to insulin in a disorder whose mechanism is progressive beta-cell loss.

Show evidence (1 reference)

PMID:34630333 SUPPORT Human Clinical

"metformin was initiated in addition to lifestyle modifications. One year later, the patient required insulin due to deterioration of his glycemic control"

Documents both the use of metformin and its failure to prevent progression to insulin dependence.

Levothyroxine Replacement

Action: thyroid hormone replacement therapy Ontology label: Hormone Replacement Therapy NCIT:C15599

Agent: levothyroxine NCIT:C62080

Standard thyroid hormone replacement for the associated hypothyroidism, started on the basis of routine biochemistry in reported children.

Show evidence (1 reference)

PMID:34630333 SUPPORT Human Clinical

"Laboratory findings confirmed hypothyroidism. Subsequently, levothyroxine was administered."

Documents levothyroxine replacement in a molecularly confirmed patient.

Recombinant Growth Hormone (of Uncertain Benefit)

Action: Pharmacotherapy NCIT:C15986

Agent: somatropin NCIT:C837

Growth hormone has been given for the severe short stature, but the reported experience is not encouraging and carries a specific caution. In one child IGF-1 normalised on growth hormone with no growth response, and treatment was stopped after a year; in another, growth hormone had been deliberately postponed because of a strong family history of diabetes, and diabetes developed five years after it was started. Growth hormone is diabetogenic, so its use in a disorder that is already destined to produce insulin deficiency needs explicit glycaemic surveillance.

Show evidence (2 references)

PMID:38279270 SUPPORT Human Clinical

"Although IGF-1 levels increased to the normal range, there was no growth response, and the treatment was discontinued after one year."

Documents the absence of a growth response to recombinant growth hormone in a DNAJC3-deficient child.

PMID:34630333 SUPPORT Human Clinical

"Recombinant Human Growth Hormine (rhGH) treatment was postponed until the age of 6.9 years due to a strong family history of diabetes."

Records the clinical caution that led to deferring growth hormone in a family at high diabetes risk; the same child developed diabetes five years after it was started.

Cochlear Implantation and Hearing Rehabilitation

Action: cochlear implantation and hearing rehabilitation Ontology label: Rehabilitation NCIT:C15315

Management of the sensorineural hearing loss, which is often the earliest neurological manifestation and the one most amenable to intervention.

Show evidence (2 references)

PMID:38279270 SUPPORT Human Clinical

"At the age of 7 years, bilateral high frequency sensorineural hearing loss (HF-SNHL) was diagnosed, requiring hearing aids."

Documents hearing amplification as the intervention used in a molecularly confirmed patient.

PMID:42353846 SUPPORT Human Clinical

"Sensorineural hearing loss was diagnosed at 9 years of age and managed with bilateral hearing aids."

A second molecularly confirmed patient managed with hearing amplification into adulthood.

Genetic Counselling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal recessive inheritance with a 25% sibling recurrence risk. Reported families are frequently consanguineous, and establishing the molecular diagnosis is what allows accurate counselling and reproductive decision-making after years of fragmented subspecialty care.

Show evidence (1 reference)

PMID:42353846 SUPPORT Human Clinical

"Establishing a specific genetic diagnosis supports appropriate genetic counseling, informs reproductive decision-making, and may help reduce prolonged diagnostic uncertainty."

States the counselling value of establishing the molecular diagnosis.

🔬

Biochemical Markers

2

Islet autoantibodies

Show evidence (1 reference)

PMID:34630333 SUPPORT Human Clinical

"Tests for markers of autoimmune diabetes were negative."

Records the negative autoantibody status that defines the diabetes as non-autoimmune.

C-peptide and insulin

Show evidence (1 reference)

PMID:40534546 SUPPORT Human Clinical

"Her laboratory findings were HbA1c 15.1 %, serum insulin 7.83 m U/L, C-peptide 0.78 μg/L."

Reports the biochemical profile at diabetic ketoacidosis presentation in a confirmed patient.

🔬

Diagnosis

6

Clinical Suspicion and Diagnostic Gestalt

The trigger for testing is antibody-negative diabetes (or unexplained hyperinsulinaemic hypoglycaemia) accompanied by two or more of short stature, ataxia, peripheral neuropathy, sensorineural hearing loss, cognitive impairment, retinal dystrophy, hypothyroidism or pancreatic atrophy. Because the components present years apart and are managed by different subspecialties, the syndrome is usually assembled retrospectively; the reported route to diagnosis is repeatedly the same, with mitochondrial diabetes and Wolfram syndrome considered and excluded first.

Show evidence (2 references)

PMID:42353846 SUPPORT Human Clinical

"Wolfram syndrome was also considered, although the absence of optic atrophy and diabetes insipidus made this diagnosis less likely."

Documents the actual diagnostic reasoning, including the features that argue against the closest mimic.

PMID:34630333 SUPPORT Human Clinical

"In individuals with diabetes whose clinical manifestations cannot be categorized as either T1D or T2D, other causes of diabetes should be considered."

States the entry point into the monogenic-diabetes workup that this disorder sits behind.

Glycaemic and Hypoglycaemia Evaluation

Two opposite evaluations are needed depending on the phase. In the hyperinsulinaemic phase, a controlled fast with paired glucose, insulin, C-peptide, free fatty acids and beta-hydroxybutyrate demonstrates inappropriate insulin secretion and a subnormal ketotic response at the time of hypoglycaemia. In the diabetic phase, HbA1c, insulin and C-peptide with negative islet autoantibodies establish non-autoimmune insulin deficiency.

Show evidence (3 references)

PMID:38279270 SUPPORT Human Clinical

"after 20 h of fasting, the blood glucose concentration dropped again to 47 mg/dL (2.6 mmol/L) with elevated insulin levels and a subnormal metabolic fasting reaction"

The fasting-study result that establishes hyperinsulinaemic hypoglycaemia in a molecularly confirmed patient.

PMID:40534546 SUPPORT Human Clinical

"Her laboratory findings were HbA1c 15.1 %, serum insulin 7.83 m U/L, C-peptide 0.78 μg/L."

The corresponding biochemistry at diabetes presentation.

PMID:34630333 SUPPORT Human Clinical

"Tests for markers of autoimmune diabetes were negative."

Confirms that autoantibody testing is the step that separates this from type 1 diabetes.

Endocrine Screening

TSH and free thyroxine, with thyroid autoantibodies to show the hypothyroidism is not autoimmune; growth velocity and IGF-1, with growth hormone stimulation testing where indicated. Both abnormalities may be present years before the diabetes, so finding them in a short child with negative thyroid antibodies is often the first clue.

Show evidence (2 references)

PMID:34630333 SUPPORT Human Clinical

"Initial investigation of patient A revealed a thyroid-stimulating hormone (TSH) level of 27.8 mIU/L and free thyroxine (FT4) level of 6.7 pmol/L"

The thyroid biochemistry that led to the diagnosis of hypothyroidism in a molecularly confirmed child.

PMID:38279270 SUPPORT Human Clinical

"IGF-1 level and body length remained persistently low"

Records the growth-axis abnormality that prompts endocrine evaluation.

Neurological and Sensory Evaluation

Brain MRI, nerve conduction studies with electromyography, and formal audiology; ophthalmological assessment where retinal involvement is suspected. Nerve conduction studies in one molecularly confirmed patient were consistent with a mild sensorimotor demyelinating peripheral neuropathy, and imaging in another showed subcortical white matter and middle cerebellar peduncle changes with prolonged tibial and ulnar conduction on EMG. Note that normal imaging does not exclude the diagnosis.

Show evidence (2 references)

PMID:38279270 SUPPORT Human Clinical

"At 9.6 years of age, nerve conduction studies were consistent with mild sensorimotor demyelinating peripheral neuropathy, both of which are known features of a DNAJC3 loss of function"

Establishes nerve conduction studies as the test that characterises the neuropathy, and its demyelinating character in that patient.

PMID:34630333 SUPPORT Human Clinical

"Brain and spine MRI demonstrated bilateral subcortical white matter intensity with bilateral middle cerebellar peduncle involvement. Electromyography revealed prolongation over the tibial and ulnar nerves."

Gives the imaging and electrophysiological findings that the neurological workup is looking for.

Pancreatic Imaging

Pancreatic MRI or ultrasound. A small, atrophic pancreas is a supportive structural finding that helps separate this disorder from other monogenic diabetes syndromes, and it can be present without exocrine insufficiency.

Show evidence (1 reference)

PMID:34630333 SUPPORT Human Clinical

"MRI revealed a small, atrophic pancreas."

The imaging finding that pancreatic assessment is looking for.

Molecular Genetic Testing With Copy-Number Analysis

Definitive diagnosis is molecular. A syndromic monogenic-diabetes or hyperinsulinism panel including DNAJC3 is reasonable first-line, and exome or genome sequencing is appropriate for a broad or neurologically dominant phenotype - both routes are represented among the reported diagnoses. The one detail that changes practice is that **the assay must include copy-number analysis**. One of the two founding families carries a homozygous multi-exon deletion of roughly 72 kb spanning DNAJC3, which a sequencing-only panel cannot see; the 2025 diagnosis was likewise made by exome sequencing combined with explicit CNV analysis. A second practical caveat is panel coverage: DNAJC3 has been present only on diabetes panels, so a child worked up primarily for ataxia or neuropathy may never have the gene tested at all.

Show evidence (3 references)

PMID:40534546 SUPPORT Human Clinical

"Exome sequencing and CNV (Copy Number Variation) analysis revealed a novel homozygous c.1244G>C (p.Arg415Pro) variant in DNAJC3 gene."

A reported diagnosis made by exome sequencing paired with copy-number analysis.

PMID:34692675 SUPPORT In Vitro

"one line having a large homozygous deletion of 72 kb spanning DNAJC3 (and the adjacent UGGT2 gene), and control fibroblasts from three healthy donors, age and sex matched"

Documents the multi-exon deletion allele that makes copy-number analysis necessary rather than optional.

PMID:34654017 SUPPORT Human Clinical

"Currently, PanelApp only includes this gene on diabetes mellitus panels. We propose DNAJC3 should be promoted from a red to a green gene on a wider number of panels to improve the diagnosis of this rare condition."

States the panel-coverage gap that causes neurologically presenting patients to be missed.

📈

Progression

4

Infancy and early childhood

Age: birth to about 5 years

Hypothyroidism and severe growth failure are often the earliest recognised problems. Where present, hyperinsulinaemic hypoglycaemia appears in this window - described around two years of age in one series - and can be diazoxide-responsive.

Show evidence (1 reference)

PMID:32738013 SUPPORT Human Clinical

"DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss."

Dates the hyperinsulinaemic phase to early childhood and records its evolution.

Mid childhood

Age: about 5 to 10 years

Sensorineural deafness is typically discovered around five to six years, and ataxia follows in the late first or early second decade. In one reported child ataxic gait began at nine years with MRI evidence of neurodegeneration.

Show evidence (1 reference)

PMID:32738013 SUPPORT Human Clinical

"Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life."

Places sensorineural deafness at five to six years and neurodegeneration within the first two decades.

Second decade

Age: about 10 to 20 years

Insulin-requiring, non-autoimmune diabetes emerges as beta-cell mass is lost, in one reported patient presenting as diabetic ketoacidosis at 15 years. The endocrine phenotype thereby inverts from insulin excess to insulin deficiency.

Show evidence (1 reference)

PMID:32738013 SUPPORT Human Clinical

"Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration."

Summarises the biphasic endocrine course that culminates in insulin deficiency.

Adulthood and diagnostic delay

The neurological features progress slowly and severity varies widely, with an adult homozygote reported to have no clinically evident neurological disease at evaluation. Because the endocrine, audiological and neurological problems are managed by different subspecialties, the unifying genetic diagnosis is frequently made late - in one report not until the age of 34.

Show evidence (2 references)

PMID:42353846 SUPPORT Human Clinical

"A delayed diagnosis occurs frequently because of fragmented subspecialty care and lack of awareness of syndromic monogenic diabetes."

Supports the observation that the unifying diagnosis is typically delayed.

PMID:42353846 SUPPORT Human Clinical

"he demonstrated no clinically evident neurological manifestations at the time of evaluation, including ataxia, despite reaching adulthood, highlighting the phenotypic variability associated with DNAJC3-related disease"

Documents an adult homozygote without clinically evident neurological disease.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Juvenile-Onset Diabetes Mellitus With Central and Peripheral Neurodegeneration:

Wolcott-Rallison syndrome

Overlapping Features Recessive EIF2AK3 (PERK) deficiency. Shares the ER-stress mechanism and the diabetes-plus-multisystem pattern, but the diabetes is neonatal or infantile and the syndrome is defined by spondyloepiphyseal dysplasia and recurrent acute liver failure, neither of which characterises DNAJC3 disease.

Show evidence (1 reference)

PMID:34654017 SUPPORT Human Clinical

"Examples include Marinesco-Sjogren and Wolcott-Rallison syndromes that share similar clinical features, manifesting neurodegenerative disease and endocrine dysfunction."

Names the two ER-chaperone syndromes that share clinical features with DNAJC3 disease.

Marinesco-Sjogren syndrome

Overlapping Features Recessive SIL1 deficiency; SIL1 is the nucleotide-exchange factor for the same BiP chaperone that p58IPK serves as a J-protein. Cerebellar ataxia, cataracts, myopathy and intellectual disability dominate; diabetes is not the presenting feature. The mechanistic proximity is close enough that Dnajc3 knockout modifies disease in a mouse model of Marinesco-Sjogren syndrome.

Show evidence (1 reference)

PMID:25466870 SUPPORT Model Organism

"This complements findings from mice in which knockout of Dnajc3 leads to diabetes and modifies disease in a neurodegenerative model of Marinesco-Sjögren syndrome."

Documents the genetic interaction between Dnajc3 and the Marinesco-Sjogren model that motivates listing it here.

Wolfram syndrome

Overlapping Features Recessive WFS1 (or CISD2) deficiency, also an ER-stress disorder, presenting with juvenile non-autoimmune diabetes mellitus, optic atrophy, diabetes insipidus and deafness. Optic atrophy and diabetes insipidus are the discriminating features; DNAJC3 disease instead carries growth hormone deficiency, hypothyroidism and prominent ataxia with upper motor neuron signs.

Show evidence (1 reference)

PMID:42353846 SUPPORT Human Clinical

"Wolfram syndrome was also considered, although the absence of optic atrophy and diabetes insipidus made this diagnosis less likely."

Names the two features whose absence argues against Wolfram syndrome in a DNAJC3 patient.

Mitochondrial diabetes with deafness

Overlapping Features Maternally inherited diabetes and deafness and other mitochondrial cytopathies are the standard alternative when diabetes is accompanied by deafness and neurodegeneration, and are explicitly the differential invoked in DNAJC3 case reports before the genetic diagnosis is made.

Show evidence (1 reference)

PMID:34630333 SUPPORT Human Clinical

"For example, mitochondrial disease is considered in patients with DM accompanied by deafness, neurodegeneration, or optic nerve atrophy"

States the diagnostic reasoning that puts mitochondrial disease in this differential.

🧫

Experimental Models

2

DNAJC3-silenced human islets and iPSC-derived beta cells CELL_LINE

RNAi knockdown of DNAJC3 in INS-1E cells, primary rat beta cells, human islets and induced pluripotent stem cell-derived beta cells. This is the system that established the apoptotic, rather than secretory, nature of the beta-cell defect and identified BIM and PUMA as the effectors.

Pathograph links

Pancreatic Beta-Cell Apoptosis via BIM and PUMA recapitulates fidelity: moderate Directly reproduces the beta-cell death mechanism, in human as well as rodent cells, and identifies its molecular effectors.

Limitations: An acute knockdown in cultured cells models neither the lifelong absence of the protein nor the tissue context of a whole pancreas, and cannot address the neurological arm at all.

Readouts

Beta-cell apoptosis after DNAJC3 knockdown

Direction: INCREASED

Interpretation: Direct measurement of the cell-death node in human and rat beta cells.

Show evidence (1 reference)

PMID:33486469 SUPPORT In Vitro

"Instead, the knockdown induced rat and human β-cell apoptosis and further sensitized cells to endoplasmic reticulum stress, triggering mitochondrial apoptosis via the pro-apoptototic Bcl-2 proteins BIM and PUMA."

Reports the measured apoptosis and its BIM/PUMA dependence.

Show evidence (1 reference)

PMID:33486469 SUPPORT In Vitro

"DNAJC3 was silenced by RNAi in INS-1E cells, primary rat β-cells, human islets, and induced pluripotent stem cell-derived β-cells."

Describes the model systems used, including human islets and iPSC-derived beta cells.

DNAJC3-deficient patient fibroblasts PRIMARY_CELL_CULTURE

Primary skin fibroblasts from affected individuals, used both to confirm absence of the protein and, by unbiased proteomics, to identify the lipid/cholesterol, mitochondrial and ER-Golgi disturbances proposed to link the chaperone defect to neurodegeneration.

Pathograph links

Disturbed Lipid Homeostasis and Mitochondrial Dysfunction measures fidelity: low Provides the proteomic and functional measurements behind this node.

Limitations: Fibroblasts are not neurons. The lipid, amyloid precursor protein and oxidative-phosphorylation findings are a plausible bridge to the neurodegenerative arm but have not been demonstrated in human neural tissue, which is why the corresponding causal edge is curated as indirect and flagged as a knowledge gap.

Readouts

Intracellular lipid accumulation in patient fibroblasts

Direction: INCREASED

Interpretation: Direct measurement of the lipid-handling defect in patient-derived cells.

Show evidence (1 reference)

PMID:34692675 SUPPORT In Vitro

"Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of..."

Reports the measured lipid accumulation and cholesterol-stress sensitivity.

Show evidence (1 reference)

PMID:34692675 SUPPORT In Vitro

"To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing."

Establishes the proteomic approach and the pathways it implicated in patient cells.

🐁

Animal Models

2

Dnajc3 (P58IPK) knockout mouse

The founding in vivo model. P58IPK-null mice develop glucosuria and hyperglycaemia gradually, driven by progressive apoptosis of pancreatic islet cells while the surviving beta cells remain functionally intact - the same dissociation between cell loss and cell function later found in human and rat beta cells silenced for DNAJC3. Young knockout mice additionally show reduced total insulin secretion capacity in vivo, with higher cellular insulin release under high-glucose stimulation, which is the model correlate of the biphasic human course.

Species

Mouse

Genotype

Dnajc3 (P58IPK) homozygous deletion

Publication

PMID:15793246

Pathograph links

Pancreatic Beta-Cell Apoptosis via BIM and PUMA partially recapitulates fidelity: moderate Reproduces the progressive islet-cell apoptosis and consequent hyperglycaemia with preserved function in surviving beta cells.

Limitations: The mouse establishes that beta-cell apoptosis follows p58IPK loss but does not itself demonstrate the BIM/PUMA route, which was shown separately in rodent and human beta cells in vitro. The knockout also does not reproduce the human multisystem neurodegeneration, so the model speaks to the endocrine arm only.

Readouts

Pancreatic islet cell apoptosis

Direction: INCREASED

Interpretation: Structural correlate of the beta-cell death node in this model.

Show evidence (1 reference)

PMID:15793246 SUPPORT Model Organism

"we generated deletion mutant mice that showed a gradual onset of glucosuria and hyperglycemia associated with increasing apoptosis of pancreatic islet cells"

Reports the measured increase in islet-cell apoptosis in the knockout.

Show evidence (1 reference)

PMID:15793246 SUPPORT Model Organism

"Insulin deficiency associated with the absence of P58(IPK) mimics beta-cell failure associated with type 1 and late-stage type 2 diabetes."

Supports treating this model as informative for the beta-cell failure node.

Hyperinsulinaemic Hypoglycaemia of Infancy and Childhood partially recapitulates fidelity: low Young knockout mice show increased insulin release per cell during high-glucose stimulation, the cellular direction predicted by the human hyperinsulinaemic phase.

Limitations: At the whole-animal level even the youngest experimentally accessible mice were already dominated by reduced total insulin secretion capacity, so the model does not reproduce hypoglycaemia; it captures a cellular tendency, not the clinical phenotype.

Readouts

Islet insulin release under high-glucose stimulation

Direction: INCREASED

Interpretation: Cellular correlate of inappropriate insulin release in the hyperinsulinaemic phase.

Show evidence (1 reference)

PMID:38279270 SUPPORT Model Organism

"However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation)."

Reports the measured increase in stimulated insulin release from knockout islets.

Show evidence (1 reference)

PMID:38279270 SUPPORT Model Organism

"In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity."

Qualifies the model - the in vivo glycaemic phenotype is already insulin-deficient at the earliest testable age, so the hyperinsulinaemic phase is not reproduced at the organism level.

p58IPK knockout mouse retina

Retinal arm of the same knockout. p58IPK is expressed in retinal ganglion cells, inner retinal neurons and photoreceptor inner segments; knockout mice lose retinal ganglion cells with age and show exaggerated ER stress and ganglion cell apoptosis after an excitotoxic challenge.

Species

Mouse

Genotype

p58IPK (Dnajc3) homozygous knockout

Publication

PMID:25655802

Pathograph links

Progressive Central and Peripheral Neurodegeneration partially recapitulates fidelity: low Demonstrates that neurons lacking p58IPK die under ER stress, providing a cell-type-specific in vivo instance of the neurodegenerative arm.

Limitations: Restricted to retinal ganglion cells; it says nothing about the cerebellar, corticospinal, peripheral nerve or auditory involvement that dominates the human phenotype, and retinal dystrophy is only an occasional human feature.

Readouts

Retinal ganglion cell number with ageing

Direction: DECREASED

Interpretation: Neuronal loss in a p58IPK-null nervous tissue.

Show evidence (1 reference)

PMID:25655802 SUPPORT Model Organism

"Mice lacking p58(IPK) exhibited increased CHOP expression and loss of RGCs with aging (8-10 months)."

Reports the measured age-related retinal ganglion cell loss in the knockout.

Show evidence (1 reference)

PMID:25655802 SUPPORT Model Organism

"Intravitreal injection of NMDA induced retinal ER stress and increased p58(IPK) expression in WT mice; this resulted in greater ER stress and enhanced RGC apoptosis in p58(IPK) KO mice."

Supports treating p58IPK as a neuroprotective factor whose loss sensitises neurons to stress-induced death.

{ }

Source YAML

click to show

name: Juvenile-Onset Diabetes Mellitus With Central and Peripheral Neurodegeneration
creation_date: "2026-08-20T00:00:00Z"
category: Mendelian
description: >-
  Juvenile-onset diabetes mellitus with central and peripheral neurodegeneration
  (DNAJC3-related syndromic monogenic diabetes) is an autosomal recessive
  disorder caused by biallelic loss-of-function variants in DNAJC3, the gene
  encoding the endoplasmic reticulum co-chaperone p58IPK (also called ERj6).
  p58IPK is a DnaJ/Hsp40-family partner of the ER chaperone BiP (GRP78) and is
  also an inhibitor of the eIF2-alpha kinases PERK and PKR. It therefore sits at
  the intersection of two functions that a professional secretory cell cannot do
  without: it helps BiP fold nascent secretory proteins, and it sets the
  set-point of the unfolded protein response so that translational attenuation
  is released once ER homeostasis is restored.

  The clinical syndrome that follows its loss is a two-organ-system disease with
  a characteristic temporal order. The endocrine arm is biphasic. In infancy and
  early childhood some affected individuals present with hyperinsulinaemic
  hypoglycaemia; the same beta cells later fail, and non-autoimmune,
  insulin-requiring diabetes emerges in the second decade, in some individuals
  accompanied by a small, atrophic pancreas on imaging. Additional endocrine
  features - severe short stature with growth hormone deficiency, and
  hypothyroidism - are common enough that a child referred for short stature and
  hypothyroidism may reach the diabetes diagnosis years later. The neurological
  arm is a slowly progressive multisystem neurodegeneration: cerebellar and gait
  ataxia, upper motor neuron signs, an axonal peripheral neuropathy,
  sensorineural hearing loss that is often the earliest neurological sign, and
  cerebral atrophy on MRI. Cognitive impairment, microcephaly, facial
  dysmorphism and retinal dystrophy are reported in a subset.

  Mechanistically the entry treats the disorder as a chaperone-capacity disease
  rather than a storage disease: no mutant client protein is retained and
  polymerised, and the primary lesion is the loss of folding and UPR-regulatory
  capacity itself. Beta cells are the most exposed tissue because of the
  extraordinary proinsulin biosynthetic load they carry, and the measured
  consequence of DNAJC3 knockdown in rodent and human beta cells is not a
  secretory defect but apoptosis - BIM- and PUMA-dependent engagement of the
  mitochondrial death pathway - which matches the progressive beta-cell loss
  seen in the Dnajc3-null mouse. The hyperinsulinaemic phase has a separate
  proposed explanation: p58IPK, acting with BiP, helps close the Sec61
  translocon, and its loss allows ER calcium to leak into the cytosol.
  Patient fibroblast proteomics additionally implicate disturbed
  lipid/cholesterol homeostasis and mitochondrial oxidative phosphorylation,
  which is the most plausible current bridge from an ER co-chaperone defect to
  the neurodegenerative arm - though that bridge is explicitly weaker than the
  beta-cell one and is curated here as an open question, not a settled chain.

  The entity must be kept separate from the other ER-stress monogenic diabetes
  syndromes it resembles. Wolcott-Rallison syndrome (EIF2AK3/PERK) and
  Marinesco-Sjogren syndrome (SIL1, a BiP nucleotide-exchange factor) share the
  BiP/PERK axis and the diabetes-plus-neurological pattern, and Wolfram syndrome
  (WFS1) shares juvenile non-autoimmune diabetes with deafness and
  neurodegeneration; DNAJC3 disease is distinguished from all three by its
  particular combination of adolescent-onset diabetes, generalised central and
  peripheral neurodegeneration, growth hormone deficiency and hypothyroidism,
  and by the absence of the epiphyseal dysplasia and infantile diabetes of
  Wolcott-Rallison. Phenotypic variability is real and wide: an adult homozygous
  for a nonsense allele has been reported with diabetes, deafness,
  hypothyroidism and short stature but no clinically evident neurological
  disease at evaluation, and one sibling pair differed in both ataxia severity
  and brain MRI findings.
disease_term:
  preferred_term: juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome
  term:
    id: MONDO:0014523
    label: juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      The presenting and diagnostically defining abnormality is endocrine:
      non-autoimmune juvenile-onset diabetes mellitus, frequently preceded by
      hyperinsulinaemic hypoglycaemia and accompanied by growth hormone
      deficiency and hypothyroidism. The disorder is classified among the
      monogenic forms of diabetes that act through the PERK arm of the
      endoplasmic reticulum stress response.
  - classification_value: NEUROLOGIC
    notes: >-
      A second assignment is made because the neurodegenerative arm is not an
      incidental complication but half of the defining syndrome name and, in the
      index family, the reason the siblings came to attention: progressive
      cerebellar ataxia, upper motor neuron damage, peripheral neuropathy,
      sensorineural hearing loss and cerebral atrophy.
parents:
- Monogenic Diabetes
- Neurodegenerative Disease
- Hereditary Ataxia
synonyms:
- DNAJC3-related syndromic monogenic diabetes
- ACPHD
- ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus
- combined cerebellar and peripheral ataxia-hearing loss-diabetes mellitus syndrome
- P58IPK deficiency
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All reported probands carry biallelic DNAJC3 variants - most often a
    homozygous nonsense, frameshift or whole-gene deletion allele in a
    consanguineous pedigree, but compound heterozygosity has also been
    described. Heterozygous carriers in the reported families are unaffected.
    Consanguinity is frequent but not required - the German proband reported in
    2024 had non-consanguineous parents. Penetrance of the multisystem phenotype
    appears high among individuals with severe biallelic loss-of-function
    alleles, but it is age-dependent and has never been formally quantified, so
    it is recorded as UNKNOWN rather than COMPLETE: the adult homozygote in
    PMID:42353846 had no clinically evident neurological disease at evaluation,
    and the sibling pair in PMID:34630333 differed in both ataxia severity and
    brain MRI at comparable ages. Expressivity is unambiguously variable.
  penetrance: UNKNOWN
  expressivity: VARIABLE
  evidence:
  - reference: PMID:25466870
    reference_title: "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings demonstrate that loss-of-function DNAJC3 mutations lead to a monogenic, recessive form of diabetes mellitus in humans."
    explanation: States the recessive mode of inheritance for loss-of-function DNAJC3 alleles.
  - reference: PMID:33486469
    reference_title: "DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They were heterozygous compound and homozygous for novel loss-of-function mutations in DNAJC3."
    explanation: Documents both compound heterozygous and homozygous biallelic genotypes in unrelated probands.
pathophysiology:
- name: Biallelic DNAJC3 Loss-of-Function Variants
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Homozygous or compound heterozygous nonsense, frameshift or whole-gene
    deletion variants in DNAJC3 abolish the protein. Reported alleles include a
    homozygous stop mutation and a homozygous whole-gene deletion in the two
    index families, and later nonsense (p.Arg393*), frameshift and missense
    (p.Arg415Pro) alleles. The absence of the protein - not a retained or
    aggregated mutant - is the primary lesion, which is why this entry models a
    chaperone-capacity failure rather than an ER storage disease.
  genes:
  - preferred_term: DNAJC3
    term:
      id: hgnc:9439
      label: DNAJC3
  genetic_context:
    gene:
      preferred_term: DNAJC3
      term:
        id: hgnc:9439
        label: DNAJC3
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic null or severely hypomorphic alleles; heterozygotes are
      unaffected. Compound heterozygosity is also reported, so the HOMOZYGOUS
      value records the commonest reported state rather than an obligatory one.
  downstream:
  - target: Loss of p58IPK Co-Chaperone Function in the Endoplasmic Reticulum
    causal_link_type: DIRECT
    description: >-
      Loss-of-function alleles result in complete absence of the DNAJC3 protein
      product in patient cells.
    evidence:
    - reference: PMID:25466870
      reference_title: "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "DNAJC3 was absent in fibroblasts from all affected subjects in both families."
      explanation: Demonstrates that the reported alleles produce no detectable protein, establishing the direct genotype-to-protein-loss link.
  evidence:
  - reference: PMID:25466870
    reference_title: "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing identified a homozygous stop mutation in DNAJC3."
    explanation: Identifies the founding genotype in the index sibship.
  - reference: PMID:42353846
    reference_title: "DNAJC3-Related Syndromic Monogenic Diabetes Without Clinically Evident Neurological Manifestations in an Adult: Expanding the Phenotypic Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis using whole-exome sequencing identified a homozygous likely pathogenic DNAJC3 variant, c.1177C>T p.(Arg393*), confirming the diagnosis of DNAJC3-related syndromic monogenic diabetes."
    explanation: A further homozygous nonsense allele, showing the recurrent truncating mutational mechanism.
  - reference: PMID:40534546
    reference_title: "A novel homozygous missense DNAJC3 variant in syndromic juvenile-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing and CNV (Copy Number Variation) analysis revealed a novel homozygous c.1244G>C (p.Arg415Pro) variant in DNAJC3 gene."
    explanation: Shows that missense as well as truncating alleles are reported, broadening the mutational spectrum.
- name: Loss of p58IPK Co-Chaperone Function in the Endoplasmic Reticulum
  biological_scale: MOLECULAR
  role: central_effector
  description: >-
    p58IPK is an ER-lumenal DnaJ/Hsp40 co-chaperone of BiP and, in parallel, an
    inhibitor of the eIF2-alpha kinases PERK and PKR that acts as the negative
    feedback limb terminating the translational-attenuation phase of the
    unfolded protein response. Its loss therefore removes two things at once:
    productive BiP-assisted folding of nascent secretory clients, and the brake
    that returns the UPR to baseline. In pancreatic beta cells BiP has been shown
    to require p58IPK for productive proinsulin folding specifically.
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: DECREASED
  molecular_functions:
  - preferred_term: BiP (HSPA5) co-chaperone binding
    term:
      id: GO:0051087
      label: protein-folding chaperone binding
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Dysregulated Unfolded Protein Response and Chronic ER Stress
    causal_link_type: DIRECT
    description: >-
      Without the p58IPK feedback limb, eIF2-alpha kinase signalling through PERK
      is no longer restrained and ER stress signalling becomes chronic rather
      than self-limiting.
    evidence:
    - reference: PMID:15793246
      reference_title: "Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "P58(IPK) (DNAJC3) is induced during ER stress and functions as a negative feedback component to inhibit eIF-2alpha signaling and attenuate the later phases of the ER stress response."
      explanation: Establishes p58IPK as the negative-feedback component whose loss leaves ER stress signalling unattenuated.
  - target: Disrupted Sec61 Translocon Gating and ER Calcium Leak
    causal_link_type: DIRECT
    description: >-
      BiP closes the Sec61 polypeptide-conducting channel with the help of its
      lumenal co-chaperones ERj3 and ERj6 (p58IPK/DNAJC3); depleting ERj6
      phenocopies BiP depletion and increases ER calcium leakage.
    evidence:
    - reference: PMID:26085089
      reference_title: "Co-chaperone Specificity in Gating of the Polypeptide Conducting Channel in the Membrane of the Human Endoplasmic Reticulum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Thus, BiP facilitates Sec61 channel closure (i.e. limits ER Ca(2+) leakage) via the Sec61 channel with the help of ERj3 and ERj6."
      explanation: Places DNAJC3/ERj6 mechanistically upstream of Sec61 channel closure and ER calcium retention.
  evidence:
  - reference: PMID:33486469
    reference_title: "DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAJC3, also known as P58IPK, is an Hsp40 family member that interacts with and inhibits PKR-like ER-localized eIF2α kinase (PERK)."
    explanation: States the PERK-inhibitory molecular function that is lost.
  - reference: PMID:25329545
    reference_title: "p58IPK is an inhibitor of the eIF2alpha kinase GCN2 and its localization and expression underpin protein synthesis and ER processing capacity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, we show that p58IPK is a general inhibitor of the eIF2α kinases in that it also interacts with GCN2."
    explanation: Extends the inhibitory role of p58IPK beyond PERK to the wider eIF2-alpha kinase family, so its loss disinhibits translational attenuation broadly.
  - reference: PMID:42224595
    reference_title: "Coordinated expression and assembly of BiP, p58(IPK), and ER chaperone complexes maximize proinsulin folding in pancreatic beta cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "BiP requires p58IPK for productive proinsulin folding, whereas nonstoichiometric BiP excess actually hinders proinsulin folding."
    explanation: Shows the BiP-p58IPK partnership is specifically required for folding the beta cell's dominant secretory client, explaining beta-cell vulnerability.
- name: Dysregulated Unfolded Protein Response and Chronic ER Stress
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    In the absence of its feedback inhibitor, PERK-mediated UPR signalling runs
    unopposed and cells sit in a state of chronic, unresolved ER stress and are
    sensitised to any further folding load. DNAJC3 disease is grouped with the
    other monogenic diabetes syndromes that act through the PERK arm of the ER
    stress response.
  biological_processes:
  - preferred_term: PERK-mediated unfolded protein response
    term:
      id: GO:0036499
      label: PERK-mediated unfolded protein response
    modifier: INCREASED
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  downstream:
  - target: Pancreatic Beta-Cell Apoptosis via BIM and PUMA
    causal_link_type: DIRECT
    description: >-
      Chronic ER stress in a cell with an extreme secretory load converts an
      adaptive response into a death signal.
    evidence:
    - reference: PMID:33486469
      reference_title: "DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Instead, the knockdown induced rat and human β-cell apoptosis and further sensitized cells to endoplasmic reticulum stress, triggering mitochondrial apoptosis via the pro-apoptototic Bcl-2 proteins BIM and PUMA."
      explanation: Directly links DNAJC3 loss and ER stress sensitisation to beta-cell apoptosis through BIM and PUMA.
  - target: Disturbed Lipid Homeostasis and Mitochondrial Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Patient fibroblasts accumulate lipid, show increased sensitivity to
      cholesterol stress, and activate the UPR, with downstream alteration of
      ER-Golgi trafficking and mitochondrial function.
    evidence:
    - reference: PMID:34692675
      reference_title: "Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein."
      explanation: Reports the measured cell-biological consequences in patient-derived cells that connect ER stress to lipid and organelle dysfunction.
  evidence:
  - reference: PMID:33486469
    reference_title: "DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report confirms previously described features and expands the clinical spectrum of syndromic DNAJC3 diabetes, one of the five monogenic forms of diabetes pertaining to the PERK pathway of the endoplasmic reticulum stress response."
    explanation: Places the disorder mechanistically within the PERK arm of the ER stress response.
  - reference: PMID:42353846
    reference_title: "DNAJC3-Related Syndromic Monogenic Diabetes Without Clinically Evident Neurological Manifestations in an Adult: Expanding the Phenotypic Spectrum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Because of their extensive insulin biosynthesis requirements, pancreatic β-cells are highly susceptible to ER stress. Loss of the co-chaperone activity of DNAJC3 leads to chronic ER stress, subsequent loss of β-cell functionality and ultimately insulin deficiency"
    explanation: Review statement of the chronic-ER-stress-to-insulin-deficiency chain and of why beta cells are the exposed tissue.
- name: Disrupted Sec61 Translocon Gating and ER Calcium Leak
  biological_scale: CELLULAR
  description: >-
    The proposed explanation for the early hyperinsulinaemic phase of the
    syndrome. p58IPK, working with BiP, assists closure of the Sec61
    polypeptide-conducting channel; without it, calcium leaks from the ER lumen
    into the cytosol of the beta cell and inappropriately drives insulin
    exocytosis. This is offered by its authors as the most likely mechanism
    rather than a demonstrated one, and is curated here as such.
  biological_processes:
  - preferred_term: intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: DECREASED
  cell_types:
  - preferred_term: pancreatic beta cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  downstream:
  - target: Hyperinsulinaemic Hypoglycaemia of Infancy and Childhood
    causal_link_type: DIRECT
    description: >-
      Cytosolic calcium rise from an ER leak is proposed to drive unregulated
      insulin release before beta-cell mass is lost.
    evidence:
    - reference: PMID:38279270
      reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We propose that calcium leakage from the ER into the cytosol, due to disrupted DNAJC3-controlled gating of the Sec61 channel, is the most likely mechanism for HH."
      explanation: States the proposed causal mechanism for the hyperinsulinaemic phase; the hedged wording is preserved deliberately.
  evidence:
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis."
    explanation: Frames the calcium-homeostasis route as the distinguishing feature of DNAJC3-related hyperinsulinism.
- name: Hyperinsulinaemic Hypoglycaemia of Infancy and Childhood
  biological_scale: ORGANISM
  description: >-
    The first, and easily missed, endocrine phase. Affected infants and young
    children can present with diazoxide-responsive hyperinsulinaemic
    hypoglycaemia, described around two years of age in one series and persisting
    into adolescence in another individual, before the beta-cell mass declines
    and the phenotype inverts to insulin deficiency.
  downstream:
  - target: Insulin Deficiency and Pancreatic Atrophy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The same beta cells that oversecrete early are progressively lost, so the
      hyperinsulinaemic phase gives way to insulin deficiency in the second
      decade.
    evidence:
    - reference: PMID:32738013
      reference_title: "Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss."
      explanation: Documents the temporal evolution from hyperinsulinaemic hypoglycaemia to insulin deficiency in the same patients.
  evidence:
  - reference: PMID:34654017
    reference_title: "Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report confirms DNAJC3 as a cause of syndromic congenital hyperinsulinaemic hypoglycaemia."
    explanation: Independent confirmation that hyperinsulinaemic hypoglycaemia belongs to the DNAJC3 phenotype.
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence."
    explanation: Shows the hyperinsulinaemic phase can be the dominant and persisting presentation rather than a transient neonatal finding.
- name: Pancreatic Beta-Cell Apoptosis via BIM and PUMA
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    The measured consequence of DNAJC3 loss in beta cells is death, not
    secretory failure. Silencing DNAJC3 in INS-1E cells, primary rat beta cells,
    human islets and iPSC-derived beta cells left insulin content and secretion
    intact but triggered apoptosis through the mitochondrial pathway, engaged by
    the BH3-only proteins BIM and PUMA. The Dnajc3-null mouse shows the
    corresponding in vivo phenotype: progressive islet-cell apoptosis with
    preserved function in the beta cells that remain.
  cell_types:
  - preferred_term: pancreatic beta cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  biological_processes:
  - preferred_term: intrinsic apoptotic signaling pathway
    term:
      id: GO:0097193
      label: intrinsic apoptotic signaling pathway
    modifier: INCREASED
  downstream:
  - target: Insulin Deficiency and Pancreatic Atrophy
    causal_link_type: DIRECT
    description: >-
      Cumulative loss of beta-cell mass produces absolute insulin deficiency.
    evidence:
    - reference: PMID:33486469
      reference_title: "DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "DNAJC3 deficiency may lead to β-cell loss through BIM- and PUMA-dependent activation of the mitochondrial pathway of apoptosis."
      explanation: States the apoptosis-to-beta-cell-loss step that produces insulin deficiency.
  evidence:
  - reference: PMID:33486469
    reference_title: "DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "DNAJC3 silencing did not impair insulin content or secretion."
    explanation: A negative result that is load-bearing here - it excludes a primary secretory defect and points to cell loss as the mechanism.
  - reference: PMID:15793246
    reference_title: "Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we generated deletion mutant mice that showed a gradual onset of glucosuria and hyperglycemia associated with increasing apoptosis of pancreatic islet cells"
    explanation: In vivo confirmation that loss of p58IPK causes progressive islet-cell apoptosis and hyperglycaemia.
  - reference: PMID:15793246
    reference_title: "Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Lack of P58(IPK) had no apparent effect on the functional integrity of viable beta-cells."
    explanation: Independent in vivo agreement with the in vitro finding that surviving beta cells function normally.
- name: Insulin Deficiency and Pancreatic Atrophy
  biological_scale: ORGANISM
  description: >-
    Progressive beta-cell loss produces non-autoimmune, insulin-requiring
    diabetes mellitus, characteristically in the second decade. Pancreatic
    imaging in at least one reported family showed a small, atrophic pancreas,
    suggesting the structural counterpart of the cellular loss. No edge is drawn
    from this node to the neurodegeneration: the neurological arm frequently
    precedes the diabetes diagnosis and is not modelled here as a diabetic
    complication but as a parallel consequence of the same upstream
    chaperone-capacity failure.
  evidence:
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with DNAJC3 mutations may possess a small atrophic pancreas."
    explanation: Reports the pancreatic structural finding accompanying the insulin deficiency.
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tests for markers of autoimmune diabetes were negative."
    explanation: Establishes the non-autoimmune character of the diabetes in a molecularly confirmed patient.
- name: Disturbed Lipid Homeostasis and Mitochondrial Dysfunction
  biological_scale: CELLULAR
  description: >-
    Unbiased proteomics of DNAJC3-deficient patient fibroblasts identified
    perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function
    and amyloid precursor protein processing. This is the best current candidate
    bridge from an ER co-chaperone defect to neuronal vulnerability, but it rests
    on fibroblast data rather than on neural tissue, and the entry treats it as a
    proposed rather than an established link.
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  downstream:
  - target: Progressive Central and Peripheral Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired oxidative phosphorylation and lipid handling are proposed to
      underlie the loss of long-lived, high-demand neurons.
    evidence:
    - reference: PMID:34692675
      reference_title: "Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Hence, we propose that the loss of DNAJC3 affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation."
      explanation: The authors' own proposed pathomechanism linking the chaperone defect to neurodegeneration-relevant cell biology; quoted with its hedge intact.
  evidence:
  - reference: PMID:34692675
    reference_title: "Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the DNAJC3 pathophysiology."
    explanation: States mitochondrial dysfunction as a major contributor to the disease mechanism.
- name: Progressive Central and Peripheral Neurodegeneration
  biological_scale: TISSUE
  description: >-
    A slowly progressive, generalised neurodegeneration affecting cerebellum,
    corticospinal tracts, peripheral nerve and the auditory system, with cerebral
    atrophy on MRI. Sensorineural hearing loss is frequently the earliest
    neurological sign, appearing around five to six years of age, well before the
    diabetes. Severity is highly variable between and within families.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:25466870
    reference_title: "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy."
    explanation: The defining clinical description of the neurological arm in the index sibship.
  - reference: PMID:32738013
    reference_title: "Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life."
    explanation: Establishes the age of onset and the sequence in which the neurological features appear.
phenotypes:
- category: Endocrine
  name: Juvenile-Onset Non-Autoimmune Diabetes Mellitus
  description: >-
    Insulin-requiring diabetes with negative islet autoantibodies, typically
    diagnosed in the second decade; presentation with diabetic ketoacidosis is
    reported.
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  evidence:
  - reference: PMID:42353846
    reference_title: "DNAJC3-Related Syndromic Monogenic Diabetes Without Clinically Evident Neurological Manifestations in an Adult: Expanding the Phenotypic Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAJC3-related syndromic monogenic diabetes is a rare autosomal recessive disorder that presents as juvenile-onset non-autoimmune diabetes; it has been associated with sensorineural hearing loss, hypothyroidism, short stature, and variable degrees of neurological manifestations."
    explanation: Characterises the diabetes as juvenile-onset and non-autoimmune and lists the associated features.
  - reference: PMID:40534546
    reference_title: "A novel homozygous missense DNAJC3 variant in syndromic juvenile-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function mutations in DNAJC3 lead to early-onset diabetes and multisystemic neurodegeneration."
    explanation: Confirms early-onset diabetes as a core feature of the DNAJC3 phenotype.
- category: Endocrine
  name: Hyperinsulinaemic Hypoglycaemia
  description: >-
    Diazoxide-responsive hyperinsulinaemic hypoglycaemia in infancy or early
    childhood, in some individuals persisting into adolescence, preceding the
    later insulin-deficient phase.
  phenotype_term:
    preferred_term: Hyperinsulinemic hypoglycemia
    term:
      id: HP:0000825
      label: Hyperinsulinemic hypoglycemia
    temporality: TRANSIENT
  evidence:
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This individual has a markedly different clinical course, with diazoxide-responsive hyperinsulinemic hypoglycemia persisting through adolescence as a dominant feature of the syndrome, marked short stature, and only subtle neurological abnormalities."
    explanation: Documents diazoxide responsiveness and persistence of the hyperinsulinaemic phase.
  - reference: PMID:34654017
    reference_title: "Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A subsequent report of two unrelated individuals extended the phenotype to include early-onset hyperinsulinaemic hypoglycaemia."
    explanation: Records the addition of hyperinsulinaemic hypoglycaemia to the recognised phenotype.
- category: Endocrine
  name: Short Stature With Growth Hormone Deficiency
  description: >-
    Severe early-onset growth failure. Growth hormone deficiency was documented
    in one series; in other individuals stimulation testing was normal and
    recombinant growth hormone produced no growth response, so short stature is
    not uniformly GH-dependent.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:32738013
    reference_title: "Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin."
    explanation: Documents severe growth failure attributed to growth hormone deficiency.
- category: Endocrine
  name: Hypothyroidism
  description: >-
    Hypothyroidism with negative thyroid autoantibodies, reported as central in
    one series and as mild primary hypothyroidism in another, requiring
    levothyroxine replacement.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:28940199
    reference_title: "Expanding the phenotype of DNAJC3 mutations: A case with hypothyroidism additionally to diabetes mellitus and multisystemic neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypothyroidism is a newly identified feature in addition to the known phenotype (diabetes with multisystemic neurodegeneration)."
    explanation: The report that added hypothyroidism to the recognised DNAJC3 phenotype.
- category: Neurologic
  name: Cerebellar and Gait Ataxia
  description: >-
    Progressive ataxia, typically apparent in the first or second decade;
    severity varies markedly, including between siblings carrying the same
    variant.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 9 years, he developed an ataxic gait. Brain magnetic resonance imaging (MRI) revealed neurodegeneration."
    explanation: Dates the onset of ataxia and links it to imaging evidence of neurodegeneration.
  - reference: PMID:34654017
    reference_title: "Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The full phenotype included neurodegeneration, ataxia, deafness, neuropathy, adolescent-onset diabetes mellitus, growth hormone deficiency and hypothyroidism."
    explanation: Lists ataxia among the core features of the syndrome.
- category: Neurologic
  name: Sensorineural Hearing Loss
  description: >-
    Sensorineural deafness, frequently the earliest neurological manifestation,
    described from around five to six years of age but in other individuals
    appearing only after the diabetes diagnosis.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:40534546
    reference_title: "A novel homozygous missense DNAJC3 variant in syndromic juvenile-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sensorineural hearing loss developed 5 months after the diagnosis of diabetes and intellectual functions were impaired."
    explanation: Documents sensorineural hearing loss in a molecularly confirmed patient and shows it can follow rather than precede the diabetes.
  - reference: PMID:32738013
    reference_title: "Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life."
    explanation: Gives the early childhood age of onset of the deafness.
- category: Neurologic
  name: Peripheral Neuropathy
  description: >-
    A peripheral neuropathy accompanying the central features, contributing with
    the ataxia to the combined cerebellar-and-peripheral ataxia that gives the
    disorder its Orphanet name.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:25466870
    reference_title: "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy."
    explanation: Lists peripheral neuropathy among the defining features of the index sibship.
- category: Neurologic
  name: Demyelinating Features on Nerve Conduction Studies
  description: >-
    Nerve conduction studies in one molecularly confirmed patient were consistent
    with a mild sensorimotor demyelinating peripheral neuropathy, and
    electromyography in another showed conduction prolongation over the tibial
    and ulnar nerves. This is curated as a separate, more specific descriptor of
    the same clinical neuropathy rather than as an additional problem; the
    demyelinating character rests on single-patient electrophysiology and should
    not be generalised to the disorder as a whole.
  phenotype_term:
    preferred_term: Demyelinating peripheral neuropathy
    term:
      id: HP:0007108
      label: Demyelinating peripheral neuropathy
  evidence:
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 9.6 years of age, nerve conduction studies were consistent with mild sensorimotor demyelinating peripheral neuropathy, both of which are known features of a DNAJC3 loss of function"
    explanation: The electrophysiological finding that characterises the neuropathy as demyelinating in that patient.
- category: Neurologic
  name: Cerebral White Matter Abnormality
  description: >-
    White matter signal change on MRI, reported both as bilateral subcortical
    white matter intensity with middle cerebellar peduncle involvement and, in a
    mildly affected individual, as small nonspecific patchy frontal white matter
    lesions.
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain and spine MRI demonstrated bilateral subcortical white matter intensity with bilateral middle cerebellar peduncle involvement."
    explanation: Reports the white matter and cerebellar peduncle imaging abnormality.
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cranial MRI, were unremarkable, except for two small, nonspecific, patchy hyperintense frontal white matter lesions"
    explanation: Shows the milder end of the imaging spectrum - explicitly nonspecific lesions on an otherwise unremarkable scan.
- category: Neurologic
  name: Upper Motor Neuron Dysfunction
  description: >-
    Upper-motor-neuron damage was one of the features that distinguished the
    index sibship from a pure cerebellar ataxia.
  phenotype_term:
    preferred_term: Upper motor neuron dysfunction
    term:
      id: HP:0002493
      label: Upper motor neuron dysfunction
  evidence:
  - reference: PMID:25466870
    reference_title: "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy."
    explanation: Documents upper motor neuron damage as part of the core neurological phenotype.
- category: Neurologic
  name: Cerebral Atrophy
  description: >-
    Cerebral atrophy on brain MRI. Imaging is not uniformly abnormal: one adult
    sibling with the same homozygous variant had a normal brain MRI at 28 years.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:25466870
    reference_title: "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy."
    explanation: Records cerebral atrophy in the index sibship.
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His elder brother, who had the same mutation, had a similar history, except that he had milder ataxia and normal brain MRI finding at the age of 28 years."
    explanation: Qualifies the finding - imaging can be normal in an adult carrying the same genotype, so cerebral atrophy is not obligate.
- category: Neurologic
  name: Cognitive Impairment
  description: >-
    Impaired intellectual functioning is reported in a proportion of affected
    individuals, alongside microcephaly in some.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:40534546
    reference_title: "A novel homozygous missense DNAJC3 variant in syndromic juvenile-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sensorineural hearing loss developed 5 months after the diagnosis of diabetes and intellectual functions were impaired."
    explanation: Documents impaired intellectual function in a molecularly confirmed patient.
- category: Structural
  name: Microcephaly
  description: Microcephaly reported in a subset of affected individuals.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:33486469
    reference_title: "DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities."
    explanation: Lists microcephaly among the features of two unrelated molecularly confirmed patients.
- category: Structural
  name: Facial Dysmorphism
  description: >-
    Dysmorphic facial features, described with a triangular face and deep-set
    eyes in one family.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:33486469
    reference_title: "DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities."
    explanation: Records facial dysmorphism as part of the reported phenotype.
- category: Structural
  name: Pancreatic Atrophy
  description: >-
    A small, atrophic pancreas on MRI, with pancreatic fibrosis, described in a
    molecularly confirmed sibship.
  phenotype_term:
    preferred_term: Small atrophic pancreas
    term:
      id: HP:0001732
      label: Abnormality of the pancreas
  evidence:
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with DNAJC3 mutations may possess a small atrophic pancreas."
    explanation: Reports pancreatic atrophy as a structural feature of the disorder.
- category: Ophthalmologic
  name: Retinal Dystrophy
  description: >-
    Retinal dystrophy is listed among the reported multisystem features.
    Supporting experimental context is that p58IPK is expressed in retinal
    ganglion cells and inner retinal neurons and that p58IPK-null mice lose
    retinal ganglion cells with age.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "biallelic DNAJC3 variants have been linked to multisystem neurodegeneration with ataxia, peripheral neuropathy, cognitive impairment, sensorineural hearing loss, and retinal dystrophy as well as short stature, hypothyroidism, facial dysmorphism, mild skeletal bone deformities, and early-onset diabetes mellitus associated with pancreatic atrophy"
    explanation: >-
      Review summary listing retinal dystrophy among the reported features.
      Tagged OTHER because it is a literature summary in an introduction rather
      than a primary observation in that paper.
  - reference: PMID:25655802
    reference_title: "Identification of p58IPK as a novel neuroprotective factor for retinal neurons."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice lacking p58(IPK) exhibited increased CHOP expression and loss of RGCs with aging (8-10 months)."
    explanation: Provides the model-organism correlate for retinal vulnerability to p58IPK loss.
genetic:
- name: DNAJC3
  notes: >-
    DNAJC3 (also P58IPK, ERj6) encodes an endoplasmic reticulum DnaJ/Hsp40
    co-chaperone of BiP and an inhibitor of the eIF2-alpha kinases PERK and PKR.
    Biallelic loss-of-function alleles are the sole established genetic cause of
    this syndrome. A heterozygous missense allele (p.His238Asn) has separately
    been proposed as a cause of autosomal dominant type 2 diabetes in Thai
    families; that is a distinct, monoallelic, non-syndromic claim and is not
    part of this entity.
  gene_term:
    preferred_term: DNAJC3
    term:
      id: hgnc:9439
      label: DNAJC3
  relationship_type: CAUSATIVE
  variants:
  - name: Homozygous nonsense alleles
    description: >-
      The commonest reported class. p.Arg194* was the founding allele in the
      index sibship and is the variant carried by one of the two patient
      fibroblast lines used for the proteomic work; p.Arg393* was reported in a
      Saudi adult. Both are predicted to truncate the protein before the
      C-terminal J domain, and the index alleles produce no detectable protein
      in patient fibroblasts.
    gene:
      preferred_term: DNAJC3
      term:
        id: hgnc:9439
        label: DNAJC3
    type: nonsense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:34692675
      reference_title: "Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We studied two fibroblast lines carrying a homozygous c.580C > T (NM_006260.4, p.Arg194∗) premature stop mutation in DNAJC3"
      explanation: Gives the exact founding nonsense allele at cDNA and protein level.
    - reference: PMID:42353846
      reference_title: "DNAJC3-Related Syndromic Monogenic Diabetes Without Clinically Evident Neurological Manifestations in an Adult: Expanding the Phenotypic Spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic analysis using whole-exome sequencing identified a homozygous likely pathogenic DNAJC3 variant, c.1177C>T p.(Arg393*), confirming the diagnosis of DNAJC3-related syndromic monogenic diabetes."
      explanation: A second, independent homozygous nonsense allele.
  - name: Frameshift alleles
    description: >-
      Two distinct frameshift alleles are reported: p.Trp186Glyfs*14, found in
      trans with a splice-acceptor variant, and a deletion in the final exon
      producing p.Lys456SerfsTer85, which elongates rather than truncates the
      protein and is predicted to abrogate the J domain. The latter is
      instructive because a last-exon frameshift escapes nonsense-mediated decay,
      so the mechanism is a non-functional J domain rather than absent message.
    gene:
      preferred_term: DNAJC3
      term:
        id: hgnc:9439
        label: DNAJC3
    type: frameshift
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:34654017
      reference_title: "Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we describe two siblings that recapitulate this extended phenotype in association with a homozygous novel mutation in the final exon of DNAJC3"
      explanation: Reports the last-exon frameshift allele in a sibling pair.
  - name: Splice-acceptor allele in compound heterozygosity
    description: >-
      A c.83-2A>G acceptor-site variant reported in trans with a frameshift
      allele in an individual whose dominant feature was diazoxide-responsive
      hyperinsulinaemic hypoglycaemia. Both were classified pathogenic by ACMG
      criteria. This allele class matters for test selection because splice-site
      variants outside the coding sequence are missed by some targeted assays.
    gene:
      preferred_term: DNAJC3
      term:
        id: hgnc:9439
        label: DNAJC3
    type: splice acceptor
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:38279270
      reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The first variant is predicted to result in the loss of an acceptor splice site, while the second variant causes a frameshift resulting in a premature stop codon that halts protein synthesis."
      explanation: Establishes the splice-acceptor plus frameshift compound-heterozygous genotype and its ACMG-pathogenic classification.
  - name: Multi-exon copy-number deletion spanning DNAJC3
    description: >-
      A homozygous deletion of about 72 kb removing DNAJC3 - and, in the family
      characterised in detail, the adjacent UGGT2 gene - was the second
      independent genotype found in the founding report. This is the allele class
      with the clearest practical consequence: a sequencing-only assay with no
      copy-number analysis will not detect it, so CNV analysis belongs in any
      diagnostic strategy for this disorder. The authors of the proteomic study
      note the UGGT2 involvement as a potential confounder but observe that all
      DNAJC3 patients present with very similar phenotypes.
    gene:
      preferred_term: DNAJC3
      term:
        id: hgnc:9439
        label: DNAJC3
    type: copy number deletion
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:25466870
      reference_title: "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Screening of a diabetes database with 226,194 individuals yielded eight phenotypically similar individuals and one family carrying a homozygous DNAJC3 deletion."
      explanation: Reports the whole-gene deletion genotype in an independent family.
    - reference: PMID:34692675
      reference_title: "Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "one line having a large homozygous deletion of 72 kb spanning DNAJC3 (and the adjacent UGGT2 gene), and control fibroblasts from three healthy donors, age and sex matched"
      explanation: Gives the size of the deletion and names the adjacent gene it also removes.
  - name: Missense alleles
    description: >-
      Rarer than the truncating classes. A homozygous p.Arg415Pro variant was
      reported in a girl presenting in diabetic ketoacidosis, and p.His238Asn is
      the separately proposed monoallelic dominant type 2 diabetes allele that
      this entry excludes from the recessive syndrome. Missense alleles are the
      class for which functional interpretation is least secure, since the
      established disease mechanism is absence of protein.
    gene:
      preferred_term: DNAJC3
      term:
        id: hgnc:9439
        label: DNAJC3
    type: missense
    clinical_significance: LIKELY_PATHOGENIC
    evidence:
    - reference: PMID:40534546
      reference_title: "A novel homozygous missense DNAJC3 variant in syndromic juvenile-onset diabetes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Exome sequencing and CNV (Copy Number Variation) analysis revealed a novel homozygous c.1244G>C (p.Arg415Pro) variant in DNAJC3 gene."
      explanation: Reports the homozygous missense allele and the assay that found it.
  evidence:
  - reference: PMID:25466870
    reference_title: "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening of a diabetes database with 226,194 individuals yielded eight phenotypically similar individuals and one family carrying a homozygous DNAJC3 deletion."
    explanation: Independent replication of the gene-disease relationship in a second family from a large diabetes cohort.
  - reference: PMID:25466870
    reference_title: "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This analysis revealed only one further loss-of-function allele in DNAJC3 and no further associations in subjects with only a subset of the features of the main phenotype."
    explanation: >-
      Establishes the rarity of DNAJC3 loss-of-function alleles and, importantly,
      that partial phenotypes were not associated with the gene - which is why
      this entry treats the full syndrome, not its components, as the entity.
  - reference: PMID:29767246
    reference_title: "DNAJC3 mutation in Thai familial type 2 diabetes mellitus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genotyping of these variants revealed that DnaJ homolog subfamily C member 3 (DNAJC3) p.H238N segregated with diabetes in the family."
    explanation: >-
      Cited to draw the boundary - a monoallelic DNAJC3 missense allele proposed
      for non-syndromic dominant type 2 diabetes, which is a different assertion
      from the recessive syndromic disorder curated here.
biochemical:
- name: Islet autoantibodies
  notes: >-
    Negative in molecularly confirmed patients, which is what separates this
    diabetes from type 1 diabetes at the bedside.
  evidence:
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tests for markers of autoimmune diabetes were negative."
    explanation: Records the negative autoantibody status that defines the diabetes as non-autoimmune.
- name: C-peptide and insulin
  notes: >-
    Low-normal insulin and C-peptide at diabetes presentation, consistent with
    insulin deficiency rather than resistance; the earlier phase of the disease
    shows the opposite pattern, with inappropriately high insulin during
    hypoglycaemia.
  evidence:
  - reference: PMID:40534546
    reference_title: "A novel homozygous missense DNAJC3 variant in syndromic juvenile-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her laboratory findings were HbA1c 15.1 %, serum insulin 7.83 m U/L, C-peptide 0.78 μg/L."
    explanation: Reports the biochemical profile at diabetic ketoacidosis presentation in a confirmed patient.
progression:
- phase: Infancy and early childhood
  age_range: birth to about 5 years
  notes: >-
    Hypothyroidism and severe growth failure are often the earliest recognised
    problems. Where present, hyperinsulinaemic hypoglycaemia appears in this
    window - described around two years of age in one series - and can be
    diazoxide-responsive.
  evidence:
  - reference: PMID:32738013
    reference_title: "Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss."
    explanation: Dates the hyperinsulinaemic phase to early childhood and records its evolution.
- phase: Mid childhood
  age_range: about 5 to 10 years
  notes: >-
    Sensorineural deafness is typically discovered around five to six years, and
    ataxia follows in the late first or early second decade. In one reported
    child ataxic gait began at nine years with MRI evidence of neurodegeneration.
  evidence:
  - reference: PMID:32738013
    reference_title: "Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life."
    explanation: Places sensorineural deafness at five to six years and neurodegeneration within the first two decades.
- phase: Second decade
  age_range: about 10 to 20 years
  notes: >-
    Insulin-requiring, non-autoimmune diabetes emerges as beta-cell mass is lost,
    in one reported patient presenting as diabetic ketoacidosis at 15 years. The
    endocrine phenotype thereby inverts from insulin excess to insulin
    deficiency.
  evidence:
  - reference: PMID:32738013
    reference_title: "Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration."
    explanation: Summarises the biphasic endocrine course that culminates in insulin deficiency.
- phase: Adulthood and diagnostic delay
  notes: >-
    The neurological features progress slowly and severity varies widely, with an
    adult homozygote reported to have no clinically evident neurological disease
    at evaluation. Because the endocrine, audiological and neurological problems
    are managed by different subspecialties, the unifying genetic diagnosis is
    frequently made late - in one report not until the age of 34.
  evidence:
  - reference: PMID:42353846
    reference_title: "DNAJC3-Related Syndromic Monogenic Diabetes Without Clinically Evident Neurological Manifestations in an Adult: Expanding the Phenotypic Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A delayed diagnosis occurs frequently because of fragmented subspecialty care and lack of awareness of syndromic monogenic diabetes."
    explanation: Supports the observation that the unifying diagnosis is typically delayed.
  - reference: PMID:42353846
    reference_title: "DNAJC3-Related Syndromic Monogenic Diabetes Without Clinically Evident Neurological Manifestations in an Adult: Expanding the Phenotypic Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "he demonstrated no clinically evident neurological manifestations at the time of evaluation, including ataxia, despite reaching adulthood, highlighting the phenotypic variability associated with DNAJC3-related disease"
    explanation: Documents an adult homozygote without clinically evident neurological disease.
diagnosis:
- name: Clinical Suspicion and Diagnostic Gestalt
  description: >-
    The trigger for testing is antibody-negative diabetes (or unexplained
    hyperinsulinaemic hypoglycaemia) accompanied by two or more of short stature,
    ataxia, peripheral neuropathy, sensorineural hearing loss, cognitive
    impairment, retinal dystrophy, hypothyroidism or pancreatic atrophy. Because
    the components present years apart and are managed by different
    subspecialties, the syndrome is usually assembled retrospectively; the
    reported route to diagnosis is repeatedly the same, with mitochondrial
    diabetes and Wolfram syndrome considered and excluded first.
  evidence:
  - reference: PMID:42353846
    reference_title: "DNAJC3-Related Syndromic Monogenic Diabetes Without Clinically Evident Neurological Manifestations in an Adult: Expanding the Phenotypic Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wolfram syndrome was also considered, although the absence of optic atrophy and diabetes insipidus made this diagnosis less likely."
    explanation: Documents the actual diagnostic reasoning, including the features that argue against the closest mimic.
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In individuals with diabetes whose clinical manifestations cannot be categorized as either T1D or T2D, other causes of diabetes should be considered."
    explanation: States the entry point into the monogenic-diabetes workup that this disorder sits behind.
- name: Glycaemic and Hypoglycaemia Evaluation
  description: >-
    Two opposite evaluations are needed depending on the phase. In the
    hyperinsulinaemic phase, a controlled fast with paired glucose, insulin,
    C-peptide, free fatty acids and beta-hydroxybutyrate demonstrates
    inappropriate insulin secretion and a subnormal ketotic response at the time
    of hypoglycaemia. In the diabetic phase, HbA1c, insulin and C-peptide with
    negative islet autoantibodies establish non-autoimmune insulin deficiency.
  evidence:
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "after 20 h of fasting, the blood glucose concentration dropped again to 47 mg/dL (2.6 mmol/L) with elevated insulin levels and a subnormal metabolic fasting reaction"
    explanation: The fasting-study result that establishes hyperinsulinaemic hypoglycaemia in a molecularly confirmed patient.
  - reference: PMID:40534546
    reference_title: "A novel homozygous missense DNAJC3 variant in syndromic juvenile-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her laboratory findings were HbA1c 15.1 %, serum insulin 7.83 m U/L, C-peptide 0.78 μg/L."
    explanation: The corresponding biochemistry at diabetes presentation.
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tests for markers of autoimmune diabetes were negative."
    explanation: Confirms that autoantibody testing is the step that separates this from type 1 diabetes.
- name: Endocrine Screening
  description: >-
    TSH and free thyroxine, with thyroid autoantibodies to show the
    hypothyroidism is not autoimmune; growth velocity and IGF-1, with growth
    hormone stimulation testing where indicated. Both abnormalities may be
    present years before the diabetes, so finding them in a short child with
    negative thyroid antibodies is often the first clue.
  evidence:
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial investigation of patient A revealed a thyroid-stimulating hormone (TSH) level of 27.8 mIU/L and free thyroxine (FT4) level of 6.7 pmol/L"
    explanation: The thyroid biochemistry that led to the diagnosis of hypothyroidism in a molecularly confirmed child.
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IGF-1 level and body length remained persistently low"
    explanation: Records the growth-axis abnormality that prompts endocrine evaluation.
- name: Neurological and Sensory Evaluation
  description: >-
    Brain MRI, nerve conduction studies with electromyography, and formal
    audiology; ophthalmological assessment where retinal involvement is
    suspected. Nerve conduction studies in one molecularly confirmed patient were
    consistent with a mild sensorimotor demyelinating peripheral neuropathy, and
    imaging in another showed subcortical white matter and middle cerebellar
    peduncle changes with prolonged tibial and ulnar conduction on EMG. Note that
    normal imaging does not exclude the diagnosis.
  evidence:
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 9.6 years of age, nerve conduction studies were consistent with mild sensorimotor demyelinating peripheral neuropathy, both of which are known features of a DNAJC3 loss of function"
    explanation: Establishes nerve conduction studies as the test that characterises the neuropathy, and its demyelinating character in that patient.
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain and spine MRI demonstrated bilateral subcortical white matter intensity with bilateral middle cerebellar peduncle involvement. Electromyography revealed prolongation over the tibial and ulnar nerves."
    explanation: Gives the imaging and electrophysiological findings that the neurological workup is looking for.
- name: Pancreatic Imaging
  description: >-
    Pancreatic MRI or ultrasound. A small, atrophic pancreas is a supportive
    structural finding that helps separate this disorder from other monogenic
    diabetes syndromes, and it can be present without exocrine insufficiency.
  evidence:
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI revealed a small, atrophic pancreas."
    explanation: The imaging finding that pancreatic assessment is looking for.
- name: Molecular Genetic Testing With Copy-Number Analysis
  description: >-
    Definitive diagnosis is molecular. A syndromic monogenic-diabetes or
    hyperinsulinism panel including DNAJC3 is reasonable first-line, and exome or
    genome sequencing is appropriate for a broad or neurologically dominant
    phenotype - both routes are represented among the reported diagnoses.

    The one detail that changes practice is that **the assay must include
    copy-number analysis**. One of the two founding families carries a homozygous
    multi-exon deletion of roughly 72 kb spanning DNAJC3, which a
    sequencing-only panel cannot see; the 2025 diagnosis was likewise made by
    exome sequencing combined with explicit CNV analysis. A second practical
    caveat is panel coverage: DNAJC3 has been present only on diabetes panels,
    so a child worked up primarily for ataxia or neuropathy may never have the
    gene tested at all.
  evidence:
  - reference: PMID:40534546
    reference_title: "A novel homozygous missense DNAJC3 variant in syndromic juvenile-onset diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing and CNV (Copy Number Variation) analysis revealed a novel homozygous c.1244G>C (p.Arg415Pro) variant in DNAJC3 gene."
    explanation: A reported diagnosis made by exome sequencing paired with copy-number analysis.
  - reference: PMID:34692675
    reference_title: "Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "one line having a large homozygous deletion of 72 kb spanning DNAJC3 (and the adjacent UGGT2 gene), and control fibroblasts from three healthy donors, age and sex matched"
    explanation: Documents the multi-exon deletion allele that makes copy-number analysis necessary rather than optional.
  - reference: PMID:34654017
    reference_title: "Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, PanelApp only includes this gene on diabetes mellitus panels. We propose DNAJC3 should be promoted from a red to a green gene on a wider number of panels to improve the diagnosis of this rare condition."
    explanation: States the panel-coverage gap that causes neurologically presenting patients to be missed.
differential_diagnoses:
- name: Wolcott-Rallison syndrome
  description: >-
    Recessive EIF2AK3 (PERK) deficiency. Shares the ER-stress mechanism and the
    diabetes-plus-multisystem pattern, but the diabetes is neonatal or infantile
    and the syndrome is defined by spondyloepiphyseal dysplasia and recurrent
    acute liver failure, neither of which characterises DNAJC3 disease.
  evidence:
  - reference: PMID:34654017
    reference_title: "Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Examples include Marinesco-Sjogren and Wolcott-Rallison syndromes that share similar clinical features, manifesting neurodegenerative disease and endocrine dysfunction."
    explanation: Names the two ER-chaperone syndromes that share clinical features with DNAJC3 disease.
- name: Marinesco-Sjogren syndrome
  description: >-
    Recessive SIL1 deficiency; SIL1 is the nucleotide-exchange factor for the
    same BiP chaperone that p58IPK serves as a J-protein. Cerebellar ataxia,
    cataracts, myopathy and intellectual disability dominate; diabetes is not the
    presenting feature. The mechanistic proximity is close enough that Dnajc3
    knockout modifies disease in a mouse model of Marinesco-Sjogren syndrome.
  evidence:
  - reference: PMID:25466870
    reference_title: "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This complements findings from mice in which knockout of Dnajc3 leads to diabetes and modifies disease in a neurodegenerative model of Marinesco-Sjögren syndrome."
    explanation: Documents the genetic interaction between Dnajc3 and the Marinesco-Sjogren model that motivates listing it here.
- name: Wolfram syndrome
  description: >-
    Recessive WFS1 (or CISD2) deficiency, also an ER-stress disorder, presenting
    with juvenile non-autoimmune diabetes mellitus, optic atrophy, diabetes
    insipidus and deafness. Optic atrophy and diabetes insipidus are the
    discriminating features; DNAJC3 disease instead carries growth hormone
    deficiency, hypothyroidism and prominent ataxia with upper motor neuron
    signs.
  evidence:
  - reference: PMID:42353846
    reference_title: "DNAJC3-Related Syndromic Monogenic Diabetes Without Clinically Evident Neurological Manifestations in an Adult: Expanding the Phenotypic Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wolfram syndrome was also considered, although the absence of optic atrophy and diabetes insipidus made this diagnosis less likely."
    explanation: Names the two features whose absence argues against Wolfram syndrome in a DNAJC3 patient.
- name: Mitochondrial diabetes with deafness
  description: >-
    Maternally inherited diabetes and deafness and other mitochondrial
    cytopathies are the standard alternative when diabetes is accompanied by
    deafness and neurodegeneration, and are explicitly the differential invoked
    in DNAJC3 case reports before the genetic diagnosis is made.
  evidence:
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For example, mitochondrial disease is considered in patients with DM accompanied by deafness, neurodegeneration, or optic nerve atrophy"
    explanation: States the diagnostic reasoning that puts mitochondrial disease in this differential.
treatments:
- name: Insulin Replacement Therapy
  description: >-
    Once the insulin-deficient phase is established, treatment is insulin. The
    diabetes is not autoimmune and is not insulin-resistant, but lifestyle
    measures and oral agents have proved insufficient in reported patients, who
    ultimately required insulin.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: insulin
      term:
        id: CHEBI:145810
        label: insulin
  evidence:
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lifestyle modification was introduced, but insulin therapy was eventually required."
    explanation: Documents that insulin therapy became necessary despite initial conservative management.
- name: Diazoxide for Hyperinsulinaemic Hypoglycaemia
  description: >-
    In the hyperinsulinaemic phase, hypoglycaemia has been reported to respond to
    diazoxide. This is phase-specific: the same patient will later need insulin,
    so the treatment target inverts over the course of the disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: diazoxide
      term:
        id: CHEBI:4495
        label: diazoxide
  target_mechanisms:
  - target: Hyperinsulinaemic Hypoglycaemia of Infancy and Childhood
    treatment_effect: INHIBITS
    description: >-
      Diazoxide opens the beta-cell KATP channel and suppresses insulin release,
      addressing the hyperinsulinaemic phase symptomatically rather than
      correcting the underlying ER calcium leak.
    evidence:
    - reference: PMID:38279270
      reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This individual has a markedly different clinical course, with diazoxide-responsive hyperinsulinemic hypoglycemia persisting through adolescence as a dominant feature of the syndrome, marked short stature, and only subtle neurological abnormalities."
      explanation: Documents diazoxide responsiveness of the hyperinsulinaemic hypoglycaemia in a DNAJC3-deficient patient.
  evidence:
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism."
    explanation: Supports active screening for the treatable hyperinsulinaemic phase.
- name: Metformin and Lifestyle Measures (Transitional Only)
  description: >-
    Reported in the early, mildly hyperglycaemic window before insulin becomes
    necessary. The published experience is that it buys time rather than
    controlling the disease: in one sibling, metformin plus lifestyle
    modification was started when diabetes appeared at 14 and insulin was
    required within a year as glycaemic control deteriorated. It should not be
    treated as an alternative to insulin in a disorder whose mechanism is
    progressive beta-cell loss.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metformin
      term:
        id: CHEBI:6801
        label: metformin
  evidence:
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "metformin was initiated in addition to lifestyle modifications. One year later, the patient required insulin due to deterioration of his glycemic control"
    explanation: Documents both the use of metformin and its failure to prevent progression to insulin dependence.
- name: Levothyroxine Replacement
  description: >-
    Standard thyroid hormone replacement for the associated hypothyroidism,
    started on the basis of routine biochemistry in reported children.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: thyroid hormone replacement therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: levothyroxine
      term:
        id: NCIT:C62080
        label: Levothyroxine
  evidence:
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings confirmed hypothyroidism. Subsequently, levothyroxine was administered."
    explanation: Documents levothyroxine replacement in a molecularly confirmed patient.
- name: Recombinant Growth Hormone (of Uncertain Benefit)
  description: >-
    Growth hormone has been given for the severe short stature, but the reported
    experience is not encouraging and carries a specific caution. In one child
    IGF-1 normalised on growth hormone with no growth response, and treatment was
    stopped after a year; in another, growth hormone had been deliberately
    postponed because of a strong family history of diabetes, and diabetes
    developed five years after it was started. Growth hormone is diabetogenic, so
    its use in a disorder that is already destined to produce insulin deficiency
    needs explicit glycaemic surveillance.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  evidence:
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although IGF-1 levels increased to the normal range, there was no growth response, and the treatment was discontinued after one year."
    explanation: Documents the absence of a growth response to recombinant growth hormone in a DNAJC3-deficient child.
  - reference: PMID:34630333
    reference_title: "Case Report: Homozygous DNAJC3 Mutation Causes Monogenic Diabetes Mellitus Associated With Pancreatic Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recombinant Human Growth Hormine (rhGH) treatment was postponed until the age of 6.9 years due to a strong family history of diabetes."
    explanation: >-
      Records the clinical caution that led to deferring growth hormone in a
      family at high diabetes risk; the same child developed diabetes five years
      after it was started.
- name: Cochlear Implantation and Hearing Rehabilitation
  description: >-
    Management of the sensorineural hearing loss, which is often the earliest
    neurological manifestation and the one most amenable to intervention.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear implantation and hearing rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  notes: >-
    Hearing aids are what the reported patients actually received; no case of
    cochlear implantation in a molecularly confirmed individual has been
    published, so implantation is listed as standard-of-care extrapolation
    rather than as reported DNAJC3-specific experience.

    That is also why this treatment keeps NCIT:C15315 (Rehabilitation) rather than the
    NCIT:C15329 (Surgical Procedure) binding used by most cochlear-implantation
    treatments in the KB. What patients received was amplification and rehabilitation;
    binding the surgical term would assert a surgical intervention that has never been
    reported in this disease.
  evidence:
  - reference: PMID:38279270
    reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 7 years, bilateral high frequency sensorineural hearing loss (HF-SNHL) was diagnosed, requiring hearing aids."
    explanation: Documents hearing amplification as the intervention used in a molecularly confirmed patient.
  - reference: PMID:42353846
    reference_title: "DNAJC3-Related Syndromic Monogenic Diabetes Without Clinically Evident Neurological Manifestations in an Adult: Expanding the Phenotypic Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sensorineural hearing loss was diagnosed at 9 years of age and managed with bilateral hearing aids."
    explanation: A second molecularly confirmed patient managed with hearing amplification into adulthood.
- name: Genetic Counselling
  description: >-
    Autosomal recessive inheritance with a 25% sibling recurrence risk. Reported
    families are frequently consanguineous, and establishing the molecular
    diagnosis is what allows accurate counselling and reproductive
    decision-making after years of fragmented subspecialty care.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42353846
    reference_title: "DNAJC3-Related Syndromic Monogenic Diabetes Without Clinically Evident Neurological Manifestations in an Adult: Expanding the Phenotypic Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Establishing a specific genetic diagnosis supports appropriate genetic counseling, informs reproductive decision-making, and may help reduce prolonged diagnostic uncertainty."
    explanation: States the counselling value of establishing the molecular diagnosis.
animal_models:
- name: Dnajc3 (P58IPK) knockout mouse
  species: Mouse
  genotype: Dnajc3 (P58IPK) homozygous deletion
  publication: PMID:15793246
  description: >-
    The founding in vivo model. P58IPK-null mice develop glucosuria and
    hyperglycaemia gradually, driven by progressive apoptosis of pancreatic islet
    cells while the surviving beta cells remain functionally intact - the same
    dissociation between cell loss and cell function later found in human and rat
    beta cells silenced for DNAJC3. Young knockout mice additionally show reduced
    total insulin secretion capacity in vivo, with higher cellular insulin
    release under high-glucose stimulation, which is the model correlate of the
    biphasic human course.
  modeled_mechanisms:
  - target: Pancreatic Beta-Cell Apoptosis via BIM and PUMA
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the progressive islet-cell apoptosis and consequent
      hyperglycaemia with preserved function in surviving beta cells.
    limitations: >-
      The mouse establishes that beta-cell apoptosis follows p58IPK loss but does
      not itself demonstrate the BIM/PUMA route, which was shown separately in
      rodent and human beta cells in vitro. The knockout also does not reproduce
      the human multisystem neurodegeneration, so the model speaks to the
      endocrine arm only.
    readouts:
    - name: Pancreatic islet cell apoptosis
      target: Pancreatic Beta-Cell Apoptosis via BIM and PUMA
      direction: INCREASED
      interpretation: Structural correlate of the beta-cell death node in this model.
      evidence:
      - reference: PMID:15793246
        reference_title: "Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we generated deletion mutant mice that showed a gradual onset of glucosuria and hyperglycemia associated with increasing apoptosis of pancreatic islet cells"
        explanation: Reports the measured increase in islet-cell apoptosis in the knockout.
    evidence:
    - reference: PMID:15793246
      reference_title: "Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Insulin deficiency associated with the absence of P58(IPK) mimics beta-cell failure associated with type 1 and late-stage type 2 diabetes."
      explanation: Supports treating this model as informative for the beta-cell failure node.
  - target: Hyperinsulinaemic Hypoglycaemia of Infancy and Childhood
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Young knockout mice show increased insulin release per cell during
      high-glucose stimulation, the cellular direction predicted by the human
      hyperinsulinaemic phase.
    limitations: >-
      At the whole-animal level even the youngest experimentally accessible mice
      were already dominated by reduced total insulin secretion capacity, so the
      model does not reproduce hypoglycaemia; it captures a cellular tendency,
      not the clinical phenotype.
    readouts:
    - name: Islet insulin release under high-glucose stimulation
      target: Hyperinsulinaemic Hypoglycaemia of Infancy and Childhood
      direction: INCREASED
      interpretation: Cellular correlate of inappropriate insulin release in the hyperinsulinaemic phase.
      evidence:
      - reference: PMID:38279270
        reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation)."
        explanation: Reports the measured increase in stimulated insulin release from knockout islets.
    evidence:
    - reference: PMID:38279270
      reference_title: "Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity."
      explanation: >-
        Qualifies the model - the in vivo glycaemic phenotype is already
        insulin-deficient at the earliest testable age, so the hyperinsulinaemic
        phase is not reproduced at the organism level.
- name: p58IPK knockout mouse retina
  species: Mouse
  genotype: p58IPK (Dnajc3) homozygous knockout
  publication: PMID:25655802
  description: >-
    Retinal arm of the same knockout. p58IPK is expressed in retinal ganglion
    cells, inner retinal neurons and photoreceptor inner segments; knockout mice
    lose retinal ganglion cells with age and show exaggerated ER stress and
    ganglion cell apoptosis after an excitotoxic challenge.
  modeled_mechanisms:
  - target: Progressive Central and Peripheral Neurodegeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Demonstrates that neurons lacking p58IPK die under ER stress, providing a
      cell-type-specific in vivo instance of the neurodegenerative arm.
    limitations: >-
      Restricted to retinal ganglion cells; it says nothing about the cerebellar,
      corticospinal, peripheral nerve or auditory involvement that dominates the
      human phenotype, and retinal dystrophy is only an occasional human feature.
    readouts:
    - name: Retinal ganglion cell number with ageing
      target: Progressive Central and Peripheral Neurodegeneration
      direction: DECREASED
      interpretation: Neuronal loss in a p58IPK-null nervous tissue.
      evidence:
      - reference: PMID:25655802
        reference_title: "Identification of p58IPK as a novel neuroprotective factor for retinal neurons."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Mice lacking p58(IPK) exhibited increased CHOP expression and loss of RGCs with aging (8-10 months)."
        explanation: Reports the measured age-related retinal ganglion cell loss in the knockout.
    evidence:
    - reference: PMID:25655802
      reference_title: "Identification of p58IPK as a novel neuroprotective factor for retinal neurons."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Intravitreal injection of NMDA induced retinal ER stress and increased p58(IPK) expression in WT mice; this resulted in greater ER stress and enhanced RGC apoptosis in p58(IPK) KO mice."
      explanation: Supports treating p58IPK as a neuroprotective factor whose loss sensitises neurons to stress-induced death.
experimental_models:
- name: DNAJC3-silenced human islets and iPSC-derived beta cells
  experimental_model_type: CELL_LINE
  description: >-
    RNAi knockdown of DNAJC3 in INS-1E cells, primary rat beta cells, human
    islets and induced pluripotent stem cell-derived beta cells. This is the
    system that established the apoptotic, rather than secretory, nature of the
    beta-cell defect and identified BIM and PUMA as the effectors.
  modeled_mechanisms:
  - target: Pancreatic Beta-Cell Apoptosis via BIM and PUMA
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Directly reproduces the beta-cell death mechanism, in human as well as
      rodent cells, and identifies its molecular effectors.
    limitations: >-
      An acute knockdown in cultured cells models neither the lifelong absence of
      the protein nor the tissue context of a whole pancreas, and cannot address
      the neurological arm at all.
    readouts:
    - name: Beta-cell apoptosis after DNAJC3 knockdown
      target: Pancreatic Beta-Cell Apoptosis via BIM and PUMA
      direction: INCREASED
      interpretation: Direct measurement of the cell-death node in human and rat beta cells.
      evidence:
      - reference: PMID:33486469
        reference_title: "DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Instead, the knockdown induced rat and human β-cell apoptosis and further sensitized cells to endoplasmic reticulum stress, triggering mitochondrial apoptosis via the pro-apoptototic Bcl-2 proteins BIM and PUMA."
        explanation: Reports the measured apoptosis and its BIM/PUMA dependence.
    evidence:
    - reference: PMID:33486469
      reference_title: "DNAJC3 deficiency induces beta-cell mitochondrial apoptosis and causes syndromic young-onset diabetes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "DNAJC3 was silenced by RNAi in INS-1E cells, primary rat β-cells, human islets, and induced pluripotent stem cell-derived β-cells."
      explanation: Describes the model systems used, including human islets and iPSC-derived beta cells.
- name: DNAJC3-deficient patient fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary skin fibroblasts from affected individuals, used both to confirm
    absence of the protein and, by unbiased proteomics, to identify the
    lipid/cholesterol, mitochondrial and ER-Golgi disturbances proposed to link
    the chaperone defect to neurodegeneration.
  modeled_mechanisms:
  - target: Disturbed Lipid Homeostasis and Mitochondrial Dysfunction
    relationship: MEASURES
    fidelity: LOW
    description: >-
      Provides the proteomic and functional measurements behind this node.
    limitations: >-
      Fibroblasts are not neurons. The lipid, amyloid precursor protein and
      oxidative-phosphorylation findings are a plausible bridge to the
      neurodegenerative arm but have not been demonstrated in human neural
      tissue, which is why the corresponding causal edge is curated as indirect
      and flagged as a knowledge gap.
    readouts:
    - name: Intracellular lipid accumulation in patient fibroblasts
      target: Disturbed Lipid Homeostasis and Mitochondrial Dysfunction
      direction: INCREASED
      interpretation: Direct measurement of the lipid-handling defect in patient-derived cells.
      evidence:
      - reference: PMID:34692675
        reference_title: "Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein."
        explanation: Reports the measured lipid accumulation and cholesterol-stress sensitivity.
    evidence:
    - reference: PMID:34692675
      reference_title: "Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing."
      explanation: Establishes the proteomic approach and the pathways it implicated in patient cells.
discussions:
- discussion_id: gap_dnajc3_neuronal_death_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does loss of a ubiquitously expressed ER co-chaperone kill cerebellar,
    corticospinal, peripheral and auditory neurons, and is that neuronal death
    mechanistically the same event as the beta-cell death?
  attaches_to:
  - pathophysiology#Progressive Central and Peripheral Neurodegeneration
  - pathophysiology#Disturbed Lipid Homeostasis and Mitochondrial Dysfunction
  rationale: >-
    The beta-cell arm is mechanistically solved to the level of effector
    proteins: DNAJC3 loss causes BIM/PUMA-dependent mitochondrial apoptosis, shown
    in rodent and human beta cells and matched by the knockout mouse. The
    neurological arm has no equivalent. The only mechanistic data are from patient
    fibroblasts (lipid accumulation, mitochondrial dysfunction, amyloid precursor
    protein handling) and from a retinal ganglion cell phenotype in the knockout
    mouse. Neither addresses cerebellum, corticospinal tract, peripheral nerve or
    cochlea, and the knockout mouse is reported for diabetes rather than for
    generalised neurodegeneration. Until this is closed, the entry deliberately
    does not assert that the neurodegeneration is a downstream consequence of the
    diabetes, nor that it shares the BIM/PUMA effector mechanism.
  proposed_experiments:
  - experiment_id: exp_dnajc3_patient_ipsc_neurons
    name: Neuronal-lineage differentiation of patient iPSC
    description: >-
      Differentiate patient-derived and isogenic-corrected iPSC into cerebellar,
      motor and sensory neuronal lineages and test whether the BIM/PUMA
      mitochondrial apoptosis route observed in beta cells operates, or whether
      the lipid/mitochondrial route observed in fibroblasts dominates.
  - experiment_id: exp_dnajc3_null_mouse_neuropathology
    name: Neuropathological characterisation of the Dnajc3-null mouse
    description: >-
      Systematically phenotype cerebellum, corticospinal tract, peripheral nerve
      and cochlea in aged Dnajc3 knockout mice, which have been studied for
      diabetes and retina but not for the full human neurological spectrum.
- discussion_id: gap_dnajc3_phenotypic_variability
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What explains the wide phenotypic variability, including an adult homozygous
    for a nonsense allele with no clinically evident neurological disease?
  attaches_to:
  - pathophysiology#Biallelic DNAJC3 Loss-of-Function Variants
  rationale: >-
    Reported genotypes are overwhelmingly null, yet outcomes differ sharply. One
    sibling pair sharing a variant differed in both ataxia severity and brain MRI;
    a 34-year-old homozygous for p.Arg393* had diabetes, deafness, hypothyroidism
    and short stature but no clinically evident neurological signs at evaluation.
    Since allelic severity cannot easily explain differences between carriers of
    the same allele, modifiers, ascertainment or the sensitivity of clinical
    examination must be doing the work, and none has been investigated. This
    matters practically, because it determines whether a newly diagnosed child
    should be counselled to expect neurodegeneration.
  proposed_experiments:
  - experiment_id: exp_dnajc3_cohort_neurophenotyping
    name: Systematic neurological phenotyping of a DNAJC3 cohort
    description: >-
      Apply uniform neurological examination, nerve conduction studies, audiometry
      and brain MRI to all reported and newly identified DNAJC3-deficient
      individuals, to establish whether apparently unaffected adults are truly
      spared or only subclinically affected.
notes: >-
  Curation boundaries and deliberate omissions.

  No conforms_to declarations are made. The two candidate modules are
  er_protein_storage_disease, which models hepatocellular retention and
  polymerisation of a mutant secretory protein and is therefore the wrong
  mechanism (nothing is stored here - a chaperone is missing), and
  loss_of_proteostasis, which is framed around age-associated network decline
  converging on misfolded-protein aggregation. DNAJC3 disease is a congenital
  chaperone-capacity deficit without a demonstrated aggregating species, so
  declaring conformance would assert an aggregation step the literature does not
  support. If a dedicated ER-stress/UPR module is created, the
  Dysregulated Unfolded Protein Response and Chronic ER Stress node is the
  natural conformance point.

  The Pancreatic Atrophy phenotype is bound to HP:0001732 (Abnormality of the
  pancreas) rather than to the more specific HP:0002594 (Pancreatic hypoplasia).
  This is deliberate. HPO defines hypoplasia as "a small organ or structure
  owing to failure to develop to normal size", and its parent HP:0100800 is
  explicitly "a congenital underdevelopment"; the DNAJC3 finding is an acquired
  atrophy with fibrosis, imaged in a child who had a normal abdominal
  ultrasound earlier in the same workup and whose beta-cell mass was
  progressively lost. Curating it as developmental hypoplasia would assert a
  prenatal origin the literature does not support, so the deliberately broader
  parent term is used with a more specific preferred_term. HPO has no
  "pancreatic atrophy" class; if one is added, this binding should be
  re-pointed. Note also that the deep-research artifact proposed "HP:0001734
  Pancreatic hypoplasia" for this phenotype - HP:0001734 is in fact Annular
  pancreas, and the suggestion was rejected.

  No causal edge is drawn from Insulin Deficiency and Pancreatic Atrophy to
  Progressive Central and Peripheral Neurodegeneration. Hearing loss and ataxia
  commonly appear years before the diabetes, so a diabetes-to-neurodegeneration
  edge would invert the observed temporal order; the two arms are modelled as
  parallel consequences of the same upstream lesion.

  Prevalence is deliberately absent. Fewer than about twenty individuals have
  been reported worldwide, spread over single-family case reports, and the one
  systematic denominator available - a screen of 226,194 individuals in a
  diabetes database - was a targeted search rather than a population prevalence
  estimate. Recording a rate from it would over-read the source.

  Frequency qualifiers are omitted from all phenotypes. With a published
  experience of this size and no cohort study reporting per-feature frequencies,
  any FrequencyEnum value would be a guess dressed as data.

  The heterozygous DNAJC3 p.His238Asn allele proposed for autosomal dominant type
  2 diabetes in Thai families is recorded in the genetic section only to mark the
  boundary; it is a monoallelic, non-syndromic claim and is not this entity.

  No GeneReviews chapter exists for DNAJC3 (PubMed searches for both the gene and
  the disease name return no GeneReviews article), so the GeneReviews phenotype
  baseline step was not applicable.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 18 citations 2026-08-20T07:22:04.594691

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Juvenile-Onset Diabetes Mellitus With Central and Peripheral Neurodegeneration
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Juvenile-Onset Diabetes Mellitus With Central and Peripheral Neurodegeneration covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Juvenile-Onset Diabetes Mellitus With Central and Peripheral Neurodegeneration

Executive summary

Disease mapping. The requested entity corresponds to autosomal-recessive DNAJC3 deficiency, most commonly called diabetes mellitus and multisystemic neurodegeneration or DNAJC3-related neuroendocrine disorder with insulin dysregulation. It is an ultra-rare syndromic monogenic diabetes caused by biallelic loss-of-function variants in DNAJC3 (P58IPK/ERdj6), an endoplasmic-reticulum (ER) BiP co-chaperone. Its core manifestations are non-autoimmune juvenile diabetes, short stature, progressive cerebellar and peripheral ataxia/neuropathy, sensorineural hearing loss, and variable cognitive, retinal, thyroid, pituitary, and pancreatic abnormalities. Some children first have hyperinsulinemic hypoglycemia (HH), producing an age-dependent, sometimes biphasic course from excessive insulin release to beta-cell failure and diabetes. (welters2024congenitalhyperinsulinismin pages 1-2, ocansey2022biallelicdnajc3variants pages 4-6)

The evidence base remains small: chiefly individual families and sibling reports, patient-derived fibroblasts, beta-cell experiments, and knockout mice. Consequently, prevalence, penetrance, phenotype frequencies, survival, and treatment-response rates cannot yet be estimated reliably.

The following table summarizes the principal evidence.

evidence domain	source/model	main finding	quantitative/example data	strength/limitation
Foundational human disease description	Human families with biallelic DNAJC3 loss	DNAJC3 deficiency causes a syndromic disorder combining juvenile/early-onset diabetes with central and peripheral neurodegeneration, often including ataxia, hearing loss, cognitive impairment, short stature, hypothyroidism, retinal findings, and pancreatic abnormalities (welters2024congenitalhyperinsulinismin pages 1-2, ocansey2022biallelicdnajc3variants pages 4-6, alwatban2021casereporthomozygous pages 4-5, alwatban2021casereporthomozygous pages 1-2)	Reported features across cases include ataxia, peripheral neuropathy, sensorineural hearing loss, retinal dystrophy, short stature, hypothyroidism, and pancreatic atrophy/hypoplasia; diabetes is generally non-autoimmune (welters2024congenitalhyperinsulinismin pages 1-2, alwatban2021casereporthomozygous pages 4-5, alwatban2021casereporthomozygous pages 1-2)	Strong syndrome-level consistency across independent families; limitation: very small number of published patients and incomplete ascertainment (ocansey2022biallelicdnajc3variants pages 4-6, alwatban2021casereporthomozygous pages 4-5)
Inheritance and causal variants	Human pedigrees/case series	Inheritance is autosomal recessive with homozygous or compound-heterozygous loss-of-function variants in DNAJC3 (alwatban2021casereporthomozygous pages 4-5, ocansey2022biallelicdnajc3variants pages 1-2, ocansey2022biallelicdnajc3variants pages 4-6)	Examples: p.Arg194; large homozygous deletion spanning exons 6-12; p.Arg393; p.Arg346*/p.Met1Val; splice-site c.393+2T>G and c.393+2T>C; c.1367_1370delAGAA (p.Lys456SerfsTer85) (ocansey2022biallelicdnajc3variants pages 4-6, alwatban2021casereporthomozygous pages 4-5, ocansey2022biallelicdnajc3variants pages 1-2, ocansey2022biallelicdnajc3variants pages 2-3)	Multiple recurrent LoF alleles support causality; limitation: no robust penetrance or population-frequency summary available from the retrieved evidence (ocansey2022biallelicdnajc3variants pages 4-6, ocansey2022biallelicdnajc3variants pages 2-3)
2024 metabolic expansion study	Human index case plus young knockout mice	Hyperinsulinemic hypoglycemia can be a primary manifestation of DNAJC3 deficiency and may precede later diabetes, supporting a biphasic endocrine phenotype (welters2024congenitalhyperinsulinismin pages 1-2, welters2024congenitalhyperinsulinismin pages 2-3, welters2024congenitalhyperinsulinismin pages 9-10)	Human case: recurrent hypoglycemia from infancy; diazoxide responsive; persisted into adolescence. Mouse: 4-week-old KO mice had reduced total in vivo insulin secretion capacity but increased high-glucose-stimulated insulin release at islet level (welters2024congenitalhyperinsulinismin pages 2-3, welters2024congenitalhyperinsulinismin pages 9-10)	Valuable because it integrates patient and mechanistic mouse data; limitation: largely driven by one newly described human case and preclinical inference (welters2024congenitalhyperinsulinismin pages 2-3, welters2024congenitalhyperinsulinismin pages 9-10)
Human endocrine natural history	Human cases/siblings	Insulin dysregulation appears age-related, with early hyperinsulinism/hypoglycemia in some patients and later hyperglycemia/diabetes in adolescence or adulthood (ocansey2022biallelicdnajc3variants pages 3-4, ocansey2022biallelicdnajc3variants pages 6-7, ocansey2022biallelicdnajc3variants pages 4-6)	Ocansey report explicitly describes a spectrum “evolving from hyperinsulinaemic hypoglycaemia to diabetes mellitus”; one prior case had infancy hypoglycemia before diabetes at age 12 years (ocansey2022biallelicdnajc3variants pages 3-4, ocansey2022biallelicdnajc3variants pages 4-6)	Suggestive and clinically important; limitation: natural history remains poorly defined because longitudinal data are sparse (ocansey2022biallelicdnajc3variants pages 6-7, ocansey2022biallelicdnajc3variants pages 4-6)
Human neurologic phenotype	Human case reports/series	Neurologic involvement affects both central and peripheral nervous systems, including cerebellar/peripheral ataxia, developmental delay or cognitive impairment, and demyelinating/sensorimotor neuropathy (ocansey2022biallelicdnajc3variants pages 1-2, ocansey2022biallelicdnajc3variants pages 3-4, ocansey2022biallelicdnajc3variants pages 2-3, alwatban2021casereporthomozygous pages 4-5)	Example findings: peroneal motor nerve conduction velocity 31 m/s indicating demyelinating neuropathy; generalized myelin maturation delay; white-matter lesions; progressive gait ataxia (ocansey2022biallelicdnajc3variants pages 3-4, ocansey2022biallelicdnajc3variants pages 2-3, welters2024congenitalhyperinsulinismin pages 2-3)	Reproducible multisystem phenotype across reports; limitation: severity is variable, and some patients show only subtle neurologic abnormalities early in life (welters2024congenitalhyperinsulinismin pages 2-3, alwatban2021casereporthomozygous pages 1-2)
Imaging/anatomical evidence	Human MRI/imaging	Pancreatic atrophy/hypoplasia and neuroimaging abnormalities are emerging components of the phenotype (alwatban2021casereporthomozygous pages 4-5, alwatban2021casereporthomozygous pages 1-2, alwatban2021casereporthomozygous pages 7-8)	Small/atrophic pancreas on MRI in two siblings; other reports note small anterior pituitary and white-matter lesions (alwatban2021casereporthomozygous pages 4-5, alwatban2021casereporthomozygous pages 1-2, ocansey2022biallelicdnajc3variants pages 2-3, welters2024congenitalhyperinsulinismin pages 2-3)	Supports multisystem structural involvement; limitation: imaging has not been performed systematically across cases (alwatban2021casereporthomozygous pages 7-8)
Molecular mechanism: normal DNAJC3 function	Human/cell biology synthesis in disease-focused papers	DNAJC3 is an ER-resident BiP co-chaperone that helps refold misfolded proteins and dampens PERK-mediated UPR signaling; deficiency disrupts ER homeostasis and promotes apoptosis (welters2024congenitalhyperinsulinismin pages 1-2, jennings2021intracellularlipidaccumulation pages 1-2)	Functions described include BiP-assisted refolding in the ER lumen and indirect inhibition of PERK/eIF2α signaling during sustained stress (welters2024congenitalhyperinsulinismin pages 1-2, jennings2021intracellularlipidaccumulation pages 1-2)	Mechanistically coherent across disease papers; limitation: mostly inferred from cell and animal systems rather than direct human tissue experiments (welters2024congenitalhyperinsulinismin pages 1-2, jennings2021intracellularlipidaccumulation pages 1-2)
Patient-cell proteomics and organelle pathology	Patient-derived fibroblasts/proteomics	Loss of DNAJC3 is associated with perturbed lipid/cholesterol metabolism, ER-Golgi dysfunction, amyloid precursor protein defects, and mitochondrial morphology/OXPHOS abnormalities (jennings2021intracellularlipidaccumulation pages 1-2)	Reported observations include intracellular lipid accumulation, increased sensitivity to cholesterol stress, UPR activation, ER-Golgi alterations, β-amyloid accumulation, and impaired mitochondrial oxidative phosphorylation (jennings2021intracellularlipidaccumulation pages 1-2)	Strong mechanistic depth from unbiased proteomics plus functional assays; limitation: fibroblasts may not fully model pancreatic beta cells or neurons (jennings2021intracellularlipidaccumulation pages 1-2)
Beta-cell injury mechanism	Human islets/cell lines/mouse	DNAJC3 deficiency promotes beta-cell dysfunction and apoptosis, providing a mechanistic basis for diabetes (welters2024congenitalhyperinsulinismin pages 1-2, welters2024congenitalhyperinsulinismin pages 7-9, jennings2021intracellularlipidaccumulation pages 1-2)	Evidence cited includes apoptosis in INS-1E cells, primary rat beta cells, and human islets; KO mice develop hypoinsulinemia and gradual hyperglycemia with age (welters2024congenitalhyperinsulinismin pages 1-2, welters2024congenitalhyperinsulinismin pages 7-9)	Cross-species convergence supports pathogenic mechanism; limitation: limited direct histopathology from affected human pancreas (welters2024congenitalhyperinsulinismin pages 7-9, alwatban2021casereporthomozygous pages 7-8)
Proposed hyperinsulinism mechanism	Human+mouse mechanistic proposal	Early hyperinsulinism may result from excessive ER-to-cytosol calcium leak via Sec61 when DNAJC3/BiP gating is impaired (welters2024congenitalhyperinsulinismin pages 9-10, welters2024congenitalhyperinsulinismin pages 1-2)	Human concept linked to diazoxide-responsive HH; mouse islets showed significantly higher insulin release during high-glucose stimulation despite lower insulin content (welters2024congenitalhyperinsulinismin pages 9-10, welters2024congenitalhyperinsulinismin pages 1-2)	Novel and disease-specific mechanistic hypothesis; limitation: calcium imaging confirmation in DNAJC3-deficient human islets is still lacking (welters2024congenitalhyperinsulinismin pages 9-10)
Real-world management	Human case reports	Management is supportive and phenotype-directed: diazoxide for HH, insulin or metformin/lifestyle for diabetes, levothyroxine for hypothyroidism, and multidisciplinary neurologic/endocrine follow-up (ocansey2022biallelicdnajc3variants pages 2-3, welters2024congenitalhyperinsulinismin pages 2-3, alwatban2021casereporthomozygous pages 4-5, alwatban2021casereporthomozygous pages 1-2)	Diazoxide doses reported from 7.5-10 mg/kg/day initially, tapered to 2.2 mg/kg/day by age 14 in one patient; one diabetic sibling initially used metformin/lifestyle then later insulin (welters2024congenitalhyperinsulinismin pages 2-3, alwatban2021casereporthomozygous pages 4-5)	Directly relevant to current care; limitation: no disease-specific trials or standardized treatment algorithms were identified (welters2024congenitalhyperinsulinismin pages 2-3, alwatban2021casereporthomozygous pages 4-5)
Growth hormone experience	Human case reports/literature review	rhGH has shown limited growth benefit and may raise concern for worsening hyperglycemia in patients with limited beta-cell reserve (alwatban2021casereporthomozygous pages 7-8, alwatban2021casereporthomozygous pages 1-2)	Off-label GH and recombinant IGF-1 showed no meaningful growth response in the 2024 case; 2021 review suggested hyperglycemia risk may outweigh benefit (welters2024congenitalhyperinsulinismin pages 2-3, alwatban2021casereporthomozygous pages 7-8)	Helpful caution for endocrine management; limitation: based on small uncontrolled observations (alwatban2021casereporthomozygous pages 7-8, welters2024congenitalhyperinsulinismin pages 2-3)
Evidence gaps	Across literature	Major gaps remain in epidemiology, formal diagnostic criteria, prognostic biomarkers, genotype-phenotype correlations, omics biomarkers in target tissues, and interventional trials (ocansey2022biallelicdnajc3variants pages 4-6, alwatban2021casereporthomozygous pages 7-8, welters2024congenitalhyperinsulinismin pages 9-10)	No prevalence/incidence estimates, no disease-specific clinical trials retrieved, and only limited longitudinal natural-history data were available (ocansey2022biallelicdnajc3variants pages 4-6, welters2024congenitalhyperinsulinismin pages 9-10)	Important for knowledge-base completeness; limitation: absence of data should not be interpreted as absence of effect or absence of clinical relevance (ocansey2022biallelicdnajc3variants pages 4-6, welters2024congenitalhyperinsulinismin pages 9-10)

Table: This table condenses the strongest currently retrieved evidence for DNAJC3-related juvenile-onset diabetes with multisystemic neurodegeneration, spanning human case reports, the 2024 human-plus-mouse study, fibroblast proteomics, management observations, and key knowledge gaps.

1. Disease information

Definition and nomenclature

This is a Mendelian, multisystem proteostasis disorder in which biallelic DNAJC3 deficiency compromises ER stress adaptation. Pancreatic beta cells and neurons appear particularly vulnerable, yielding endocrine dysfunction plus central and peripheral neurodegeneration. The foundational report described diabetes with multisystemic neurodegeneration; later reports broadened the phenotype to hypothyroidism, pancreatic atrophy, retinal disease, neutropenia, and congenital/childhood HH. (alwatban2021casereporthomozygous pages 4-5, ocansey2022biallelicdnajc3variants pages 1-2, welters2024congenitalhyperinsulinismin pages 1-2)

Synonyms:

DNAJC3 deficiency / DNAJC3-related disorder
Diabetes mellitus and multisystemic neurodegeneration
Syndromic juvenile-onset diabetes due to DNAJC3
DNAJC3-related neuroendocrine developmental disorder with insulin dysregulation
P58IPK deficiency

Identifiers. OMIM commonly catalogs the phenotype as Diabetes mellitus and multisystemic neurodegeneration, autosomal recessive (DMND), generally reported as OMIM 616192, and DNAJC3 as OMIM 601184. These numerical mappings should be revalidated against the live OMIM record before database ingestion because the retrieved papers did not reproduce the identifiers. A disease-specific MONDO, Orphanet, MeSH, ICD-10, or ICD-11 code was not established in the retrieved primary literature; therefore, assigning a generic diabetes or ataxia code would lose the syndromic meaning. Recommended knowledge-base representation is a DNAJC3-related monogenic disease concept linked to its component diabetes, neuropathy, ataxia, deafness, and endocrine phenotypes.

Source granularity. The available clinical information comes from aggregated case reports and very small family series, not EHR-scale cohorts. For example, the 2021 report described two Saudi brothers, while the 2022 paper described two affected siblings identified through the 100,000 Genomes Project. (alwatban2021casereporthomozygous pages 4-5, ocansey2022biallelicdnajc3variants pages 2-3, ocansey2022biallelicdnajc3variants pages 6-7)

2. Etiology, risk, and protective factors

Causal factor

The established cause is germline biallelic loss of DNAJC3 function, inherited autosomal recessively. Reported alleles include:

c.580C>T, p.Arg194Ter;
a homozygous approximately 72.7-kb deletion involving exons 6–12 and neighboring sequence;
c.1177C>T, p.Arg393Ter;
compound heterozygous c.1036C>T, p.Arg346Ter / c.1A>G, p.Met1Val;
splice variants c.393+2T>G and c.393+2T>C;
c.1367_1370delAGAA, p.Lys456SerfsTer85, which elongates and disrupts the J-domain-containing protein. (alwatban2021casereporthomozygous pages 4-5, ocansey2022biallelicdnajc3variants pages 1-2, ocansey2022biallelicdnajc3variants pages 4-6)

These are predominantly nonsense, frameshift, splice-disrupting, or multiexon-deletion alleles consistent with loss of function. The disease is germline, not somatic. Individual ClinVar classifications and gnomAD frequencies were not available in the retrieved full text and should be imported variant-by-variant rather than inferred. The heterozygous p.His238Asn allele proposed in familial type 2 diabetes has weak evidence: it was also found in unaffected individuals and occurs at low population frequency, arguing against treating heterozygous DNAJC3 variation as an established dominant cause. (jennings2021intracellularlipidaccumulation pages 1-2)

Risk and protective factors

Genetic risk: two pathogenic/likely pathogenic alleles in trans; consanguinity increases the probability of homozygosity. Several reported families were consanguineous. (alwatban2021casereporthomozygous pages 1-2, ocansey2022biallelicdnajc3variants pages 2-3)
Family history: an affected sibling or known carrier parents substantially increases prior probability; recurrence risk for two carrier parents is 25% per conception.
Modifiers: no validated modifier genes, protective alleles, or quantitative penetrance modifiers are known.
Environment/lifestyle: no toxin, infection, diet, smoking, occupational, or geographic exposure is established as causal. Ordinary metabolic stress may influence beta-cell reserve but is not a primary cause.
Possible gene–treatment interaction: growth hormone (GH) antagonizes insulin action and could unmask hyperglycemia in a person with limited beta-cell reserve. In six reported treated patients, however, hyperglycemia persisted or recurred after GH withdrawal, confirming underlying disease rather than GH as the cause. (alwatban2021casereporthomozygous pages 7-8)
Protective factors: no disease-preventing environmental intervention is demonstrated. Early detection and treatment of hypoglycemia protects against secondary neurologic injury but does not correct DNAJC3 deficiency.

3. Phenotypes

Because published numbers are extremely small and ascertainment differs among reports, frequencies below are qualitative rather than population estimates.

Phenotype	Type, onset, course and impact	Suggested HPO term
Non-autoimmune diabetes mellitus	Usually childhood/adolescence; insidious and progressive, with residual insulin initially but eventual insulin requirement. GAD2 antibodies were absent in four of five foundational subjects; the original article required an erratum to correct this point. (synofzik2015absenceofbip pages 1-1)	Juvenile-onset diabetes mellitus; HP:0000819 Diabetes mellitus
Hyperinsulinemic hypoglycemia	Infancy/childhood; diazoxide-responsive; may remit before later diabetes, although a 2024 patient retained HH through adolescence. Hypoglycemia can be asymptomatic. (ocansey2022biallelicdnajc3variants pages 6-7, welters2024congenitalhyperinsulinismin pages 2-3)	HP:0000825 Hyperinsulinemia; HP:0001943 Hypoglycemia; HP:0001985 Hypoketotic hypoglycemia
Severe short stature/growth failure	Usually evident in infancy; persistent and often severe. One child remained approximately −4 SD despite GH and IGF-1. (welters2024congenitalhyperinsulinismin pages 2-3)	HP:0004322 Short stature; HP:0001510 Growth delay
Cerebellar/peripheral ataxia	Childhood onward; variable but often progressive, impairing walking and long-distance mobility. (alwatban2021casereporthomozygous pages 4-5, alwatban2021casereporthomozygous pages 7-8)	HP:0001251 Ataxia; HP:0002072 Cerebellar ataxia; HP:0002131 Episodic ataxia is not characteristic
Sensorimotor neuropathy	Childhood/adolescence; demyelinating or mixed sensorimotor involvement. Peroneal motor conduction velocity was 31 m/s in one child. (ocansey2022biallelicdnajc3variants pages 3-4)	HP:0000763 Peripheral neuropathy; HP:0003431 Sensorimotor neuropathy; HP:0007108 Demyelinating peripheral neuropathy
Sensorineural hearing loss	Common across reported families; generally bilateral, childhood onset, and functionally important for language/education. (alwatban2021casereporthomozygous pages 4-5, welters2024congenitalhyperinsulinismin pages 1-2)	HP:0000407 Sensorineural hearing impairment; HP:0000365 Hearing impairment
Developmental/cognitive impairment	Variable global developmental delay, delayed language, learning difficulties, or intellectual disability. (alwatban2021casereporthomozygous pages 1-2, ocansey2022biallelicdnajc3variants pages 2-3)	HP:0001263 Global developmental delay; HP:0001249 Intellectual disability; HP:0000750 Delayed speech and language development
Hypothyroidism	Usually primary, sometimes detected in infancy; generally manageable with levothyroxine. (alwatban2021casereporthomozygous pages 1-2, welters2024congenitalhyperinsulinismin pages 2-3)	HP:0000821 Hypothyroidism
Microcephaly	Reported as consistent in some families, but not universal across the full spectrum. (ocansey2022biallelicdnajc3variants pages 4-6)	HP:0000252 Microcephaly
Retinal/ocular disease	Retinal dystrophy, rod–cone dysfunction, myopia, coloboma, or other ocular findings in selected patients; variable expressivity. (ocansey2022biallelicdnajc3variants pages 2-3, ocansey2022biallelicdnajc3variants pages 4-6)	HP:0000556 Retinal dystrophy; HP:0000608 Retinal degeneration; HP:0000545 Myopia; HP:0000588 Optic nerve coloboma if applicable
Pancreatic hypoplasia/atrophy	MRI finding in two brothers; may reflect abnormal development plus progressive tissue loss. Exocrine function can remain normal. (alwatban2021casereporthomozygous pages 4-5, alwatban2021casereporthomozygous pages 7-8)	HP:0012092 Abnormal pancreas morphology; HP:0001734 Pancreatic hypoplasia
White-matter/myelin abnormalities	Variable MRI finding: nonspecific frontal lesions or delayed myelin maturation; MRI can also be normal despite ataxia. (alwatban2021casereporthomozygous pages 1-2, ocansey2022biallelicdnajc3variants pages 2-3, welters2024congenitalhyperinsulinismin pages 2-3)	HP:0002500 Abnormal cerebral white matter morphology; HP:0012448 Delayed myelination
Pituitary hypoplasia	Small anterior pituitary in the 2022 siblings, but pituitary hormone function may be normal. (ocansey2022biallelicdnajc3variants pages 1-2, ocansey2022biallelicdnajc3variants pages 4-6)	HP:0012504 Pituitary hypoplasia
Neutropenia	Persistent neutrophils 0.6–0.8 ×10⁹/L in the 2022 siblings; a possible expanded phenotype, not established as core. (ocansey2022biallelicdnajc3variants pages 2-3)	HP:0001875 Neutropenia

Quality of life. No validated EQ-5D, SF-36, or PROMIS cohort data exist. One severely affected young adult could not complete high school, used a wheelchair for long distances, and required help with outdoor activities; his more mildly affected brother completed high school, worked, drove, and remained independent. This illustrates marked variable expressivity rather than a measurable average burden. (alwatban2021casereporthomozygous pages 7-8)

4. Genetic and molecular information

Causal gene: DNAJC3, encoding DnaJ heat-shock-protein family member C3, also known as P58IPK or ERdj6. Suggested annotations include HGNC symbol DNAJC3 and protein-function terms for ER chaperone binding and unfolded-protein response regulation; the precise HGNC numeric identifier should be retrieved directly from HGNC.

DNAJC3 contains an N-terminal substrate-binding region and a C-terminal J domain. It binds hydrophobic regions of misfolded ER proteins; ATP-dependent J-domain interaction activates the HSPA5/BiP folding cycle. DNAJC3 also restrains PERK signaling, thereby limiting eIF2α phosphorylation and helping restart translation after stress. (welters2024congenitalhyperinsulinismin pages 1-2, jennings2021intracellularlipidaccumulation pages 1-2)

Functional consequence: established disease alleles largely cause absent or severely impaired protein, defective BiP co-chaperone activity, maladaptive UPR signaling, and stress-induced apoptosis. The p.Lys456SerfsTer85 allele is predicted to alter the J domain and prevent effective BiP ATPase activation. (ocansey2022biallelicdnajc3variants pages 1-2, ocansey2022biallelicdnajc3variants pages 4-6)

Chromosomal, epigenetic, and modifier information: no recurrent aneuploidy, translocation, inversion, repeat expansion, disease-specific methylation signature, or validated modifier gene has been established. One affected child had normal 46,XX karyotype, array-CGH, and Prader–Willi-region methylation testing during an earlier diagnostic work-up. (welters2024congenitalhyperinsulinismin pages 2-3)

5. Environmental information

This is not an infectious, toxic, occupational, nutritional, or lifestyle-induced disease. No pathogen or environmental trigger is required. Rotavirus infection led to detection—not proof of causation—of recurrent hypoglycemia in one infant. (welters2024congenitalhyperinsulinismin pages 2-3)

Lifestyle measures can support diabetes care but do not remove the molecular defect. Metformin and lifestyle modification temporarily managed diabetes in one patient before insulin was required. (alwatban2021casereporthomozygous pages 4-5)

6. Mechanism and pathophysiology

Upstream causal chain

Biallelic DNAJC3 loss reduces ER-resident P58IPK/ERdj6 activity.
BiP-assisted protein folding and ER recovery fail, while PERK–eIF2α stress signaling is inadequately restrained.
Secretory cells with high protein-folding demand—notably pancreatic beta cells and selected neurons—develop maladaptive ER stress.
Downstream lipid/cholesterol dysregulation, ER–Golgi disturbance, mitochondrial dysfunction, impaired oxidative phosphorylation, and apoptosis reduce beta-cell and neuronal survival.
Beta-cell loss causes hypoinsulinemia and diabetes; neuronal injury produces ataxia, neuropathy, hearing loss, and cognitive manifestations. (welters2024congenitalhyperinsulinismin pages 1-2, jennings2021intracellularlipidaccumulation pages 1-2)

Biphasic insulin mechanism: current 2024 model

The 2024 study proposed an additional early mechanism. Sec61 transports nascent polypeptides and can leak ER calcium; luminal BiP promotes channel closure. Deletion of DNAJC3 or DNAJB11 increases Sec61-mediated leakage. In beta cells, excess ER-to-cytosol Ca²⁺ may initially provoke inappropriate insulin exocytosis and HH. With persistent ER stress, apoptosis reduces beta-cell mass, shifting the phenotype toward insulin deficiency and diabetes. (welters2024congenitalhyperinsulinismin pages 9-10)

This remains a strong mechanistic hypothesis, not fully demonstrated in human beta cells: direct calcium imaging in DNAJC3-deficient human islets is still needed. The article accurately summarizes its novelty as: “This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis.” (welters2024congenitalhyperinsulinismin pages 1-2)

Molecular profiling

Patient-fibroblast proteomics and functional studies found perturbed lipid metabolism, mitochondrial bioenergetics, ER–Golgi function, and amyloid-beta processing. Cells accumulated lipids, were unusually sensitive to cholesterol stress, activated the UPR, showed altered ER–Golgi machinery and APP processing, and had abnormal mitochondrial morphology and oxidative phosphorylation. The authors’ abstract states: “the loss of DNAJC3 affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation.” (jennings2021intracellularlipidaccumulation pages 1-2)

No disease-specific single-cell, spatial-transcriptomic, epigenomic, metabolomic, or lipidomic cohort is currently available. The fibroblast proteome may identify pathways but cannot substitute for affected human islets, cerebellum, peripheral nerve, cochlea, or retina.

Suggested ontology annotations

GO biological process: protein folding in ER; response to ER stress; unfolded protein response; regulation of translation; calcium-ion homeostasis; intrinsic apoptotic signaling in response to ER stress; regulation of insulin secretion; mitochondrial organization; oxidative phosphorylation; lipid/cholesterol homeostasis.
GO cellular component: endoplasmic-reticulum lumen; ER membrane; Sec61 translocon complex; mitochondrion; Golgi apparatus.
Cell Ontology: pancreatic beta cell (CL:0000169); neuron (CL:0000540); peripheral sensory neuron; motor neuron; cerebellar neuron/Purkinje cell; Schwann cell; retinal photoreceptor; cochlear hair cell; thyroid follicular cell.
Chemical ontology: calcium ion (CHEBI:29108), glucose (CHEBI:17234), insulin, cholesterol (CHEBI:16113).

7. Anatomical structures affected

Primary organs/systems:

Endocrine pancreas, especially islet beta cells; pancreatic hypoplasia/atrophy can be visible on MRI.
Central nervous system, including cerebellar circuitry and cerebral white matter.
Peripheral nervous system, involving sensory and motor axons and/or myelin.
Inner ear/auditory pathway, causing bilateral sensorineural loss.
Retina, variably involving rod and cone photoreceptors.
Thyroid and pituitary, with primary hypothyroidism and occasional small anterior pituitary. (ocansey2022biallelicdnajc3variants pages 3-4, ocansey2022biallelicdnajc3variants pages 2-3, welters2024congenitalhyperinsulinismin pages 1-2)

Secondary involvement: skeletal growth, cognition, mobility, education, and psychosocial independence. Classic diabetic microvascular complications have not been systematically quantified.

Suggested UBERON sites: pancreas/islet of Langerhans; brain/cerebellum/cerebral white matter; peripheral nerve; cochlea; retina; thyroid gland; pituitary gland. Subcellular site: ER lumen and membrane are upstream; mitochondria and ER–Golgi machinery are important downstream compartments. No consistent lateralization is reported; hearing, neuropathy, and retinal manifestations are generally bilateral/systemic.

8. Temporal development

The disorder is chronic and lifelong, but its components emerge asynchronously:

Infancy: growth failure, hypothyroidism, developmental delay, and HH may appear. In the 2024 case, recurrent glucose below 40 mg/dL was first recognized at nine months. (welters2024congenitalhyperinsulinismin pages 2-3)
Childhood: short stature persists; hearing loss, developmental/learning problems, retinal findings, ataxia, and neuropathy emerge variably.
Adolescence: diabetes commonly becomes apparent as beta-cell reserve declines. Documented onsets include ages 11, 12, and 14 years. (alwatban2021casereporthomozygous pages 4-5, alwatban2021casereporthomozygous pages 1-2, ocansey2022biallelicdnajc3variants pages 4-6)
Adulthood: neurologic disability may progress, although severity is variable and MRI may remain normal in a mildly affected adult. (alwatban2021casereporthomozygous pages 1-2)

The most distinctive trajectory is early HH → remission or declining diazoxide requirement → later hyperglycemia/diabetes, but not every patient is recognized in the hypoglycemic phase, and HH persisted to age 14 in the 2024 report. (ocansey2022biallelicdnajc3variants pages 6-7, welters2024congenitalhyperinsulinismin pages 2-3)

There is no known spontaneous molecular remission. Treated endocrine abnormalities can be controlled, but neurodegeneration and beta-cell loss are not known to reverse.

9. Inheritance and population

Inheritance: autosomal recessive.
Penetrance: likely high for a multisystem phenotype among people with severe biallelic loss-of-function alleles, but age-dependent and not formally quantified.
Expressivity: clearly variable, including neurological severity, MRI findings, retinal disease, and timing of dysglycemia. (alwatban2021casereporthomozygous pages 1-2, ocansey2022biallelicdnajc3variants pages 4-6)
Anticipation: not expected and not reported.
Germline mosaicism: not documented; a small residual risk remains theoretically possible after an apparently de novo event.
Consanguinity: important in multiple reports but not required; the 2024 patient had non-consanguineous German parents. (ocansey2022biallelicdnajc3variants pages 2-3, welters2024congenitalhyperinsulinismin pages 2-3)
Founder effects/carrier frequency: none established.
Sex ratio: no reliable estimate or demonstrated sex bias.
Geography/ancestry: affected families have included Turkish, Middle Eastern/Arab, British and German backgrounds, supporting worldwide occurrence rather than geographic restriction. (alwatban2021casereporthomozygous pages 4-5, welters2024congenitalhyperinsulinismin pages 2-3, ocansey2022biallelicdnajc3variants pages 4-6)

No population prevalence, incidence per 100,000, or carrier-frequency estimate is available. The safest classification is ultra-rare, with published evidence limited to a small number of families.

10. Diagnostics

Clinical suspicion

Consider DNAJC3 deficiency in a child or young adult with antibody-negative diabetes or HH plus two or more of short stature, ataxia, neuropathy, hearing loss, developmental impairment, retinal dystrophy, hypothyroidism, or pancreatic atrophy. The overlap with mitochondrial diabetes, Wolfram syndrome, Wolcott–Rallison syndrome, Marinesco–Sjögren syndrome, and complex inherited neuropathies is substantial. DNAJC3 should specifically enter the differential for diabetes–deafness–neurodegeneration presentations. (alwatban2021casereporthomozygous pages 6-7, alwatban2021casereporthomozygous pages 7-8)

Recommended evaluation

Glycemic assessment: fasting/random glucose, HbA1c, oral or mixed-meal testing as appropriate, C-peptide, insulin, and diabetes autoantibodies.
During hypoglycemia: paired glucose, insulin, C-peptide, beta-hydroxybutyrate, free fatty acids, cortisol and growth hormone; glucagon response; acylcarnitines, amino acids, and urine organic acids to exclude metabolic mimics. In the 2024 patient, glucose 52 mg/dL was accompanied by insulin 6.5 mU/L, C-peptide 1.4 ng/mL and beta-hydroxybutyrate 0.1 mmol/L at age 14. (welters2024congenitalhyperinsulinismin pages 2-3)
Endocrine: TSH/free T4, growth velocity, IGF-1 and targeted pituitary testing.
Neurologic: examination, developmental/neuropsychological testing, brain MRI, EMG and nerve-conduction studies.
Sensory: formal audiology; ophthalmologic examination, optical coherence tomography and electroretinography where indicated.
Anatomical: pancreatic MRI or ultrasound; MRI may disclose a small/atrophic pancreas even with preserved exocrine function. (alwatban2021casereporthomozygous pages 4-5, alwatban2021casereporthomozygous pages 7-8)

Genetic testing strategy

First-line: an NGS syndromic monogenic-diabetes/HH panel that includes DNAJC3, ideally with copy-number analysis.
If the phenotype is neurologically dominant: a complex ataxia/neuropathy panel must also include DNAJC3.
WES or WGS is appropriate when panel testing is negative or the phenotype is broad. WES diagnosed the Saudi siblings; WGS identified the 2022 family. (alwatban2021casereporthomozygous pages 1-2, ocansey2022biallelicdnajc3variants pages 2-3)
Confirm variants and segregation with Sanger sequencing or validated orthogonal methods.
Use deletion/duplication analysis for multiexon CNVs. Standard karyotype, CMA, FISH, mitochondrial DNA, and repeat-expansion tests do not directly detect the usual cause unless used to investigate alternatives.
RNA studies may clarify splice variants; no validated diagnostic proteomic, metabolomic, or methylation assay exists.

The 2024 research panel achieved mean target coverage of 624× with about 99% of targets covered at least 20×, illustrating high-sensitivity targeted sequencing rather than a required clinical threshold. (welters2024congenitalhyperinsulinismin pages 9-10)

Differential diagnosis

Important alternatives include WFS1/CISD2 Wolfram syndrome; EIF2AK3 Wolcott–Rallison syndrome; SIL1 Marinesco–Sjögren syndrome; mitochondrial m.3243A>G diabetes-deafness; WFS1, OPA1 and other deafness/optic-neuropathy disorders; HNF1B and CEL-related pancreatic disease; hereditary ataxias and Charcot–Marie–Tooth disorders; and FICD-related BiP dysregulation. Distinguishing clues for DNAJC3 are autosomal-recessive inheritance, severe short stature, combined central/peripheral neurodegeneration, non-autoimmune diabetes or preceding HH, and pancreatic atrophy.

No consensus diagnostic criteria or population/newborn screening program exists. Cascade testing is appropriate once familial variants are known.

11. Outcome and prognosis

Quantitative survival, life-expectancy, mortality, and five- or ten-year outcome data are unavailable. Published patients have survived into adulthood, but the cohort is too small and young to define lifespan.

Major morbidity comes from progressive gait impairment/neuropathy, hearing loss, developmental or cognitive disability, visual disease, severe short stature, hypoglycemic brain-injury risk, and lifelong diabetes. One adult required a wheelchair for long distances and assistance with outside activities, whereas his brother remained independently mobile and employed, demonstrating broad prognostic variability. (alwatban2021casereporthomozygous pages 7-8)

Likely adverse prognostic indicators include early/severe neurologic involvement, recurrent untreated hypoglycemia, profound hearing/visual loss, advanced pancreatic atrophy, and low C-peptide, but none is validated as a prognostic biomarker. No disease-specific biomarker predicts neurologic progression.

12. Treatment and current applications

There is no approved disease-modifying, gene, cell, RNA, or targeted UPR therapy for DNAJC3 deficiency and no disease-specific interventional clinical trial was identified.

Current real-world management

HH: regular feeding/avoidance of prolonged fasting, glucose monitoring and diazoxide when responsive; chlorothiazide may accompany diazoxide. One patient received 7.5–10 mg/kg/day in childhood, tapered to 2.2 mg/kg/day by age 14 while maintaining glucose above 70 mg/dL. Monitor fluid retention, hypertrichosis, pulmonary hypertension and blood counts according to standard CHI practice. (ocansey2022biallelicdnajc3variants pages 2-3, welters2024congenitalhyperinsulinismin pages 2-3)
Diabetes: individualized nutrition, continuous glucose monitoring where accessible, and insulin when secretion becomes inadequate. Metformin/lifestyle measures may temporarily suffice in mild early hyperglycemia but did not prevent later insulin need in a reported patient. (alwatban2021casereporthomozygous pages 4-5)
Hypothyroidism: levothyroxine.
Hearing loss: hearing aids, educational accommodations, and cochlear-implant assessment where appropriate.
Neurologic disability: physical and occupational therapy, gait aids, orthotics, fall prevention, wheelchair support, and neuropathic-pain treatment.
Development/communication: speech-language therapy, neuropsychology, individualized education, and psychosocial support.
Vision: low-vision and retinal surveillance services.
Nutrition: dietetic review for growth failure and diabetes/HH balance.

GH/IGF-1 caution. GH or recombinant IGF-1 produced little or no linear-growth response in reported patients. Because GH can worsen hyperglycemia in a person with limited beta-cell reserve, the 2021 authors argued that risk may outweigh benefit unless true GH deficiency is demonstrated and glycemia is monitored closely. (welters2024congenitalhyperinsulinismin pages 2-3, alwatban2021casereporthomozygous pages 7-8)

Suggested NCI Thesaurus intervention concepts include insulin therapy, diazoxide treatment, thyroid-hormone replacement, glucose monitoring, physical therapy, occupational therapy, hearing aid, cochlear implantation, and genetic counseling; exact NCIT codes should be resolved against the current NCIT release.

13. Prevention

Primary prevention of disease in an already conceived affected individual is unavailable. Reproductive options for a known carrier couple include genetic counseling, partner/cascade testing, prenatal diagnosis, and preimplantation genetic testing for monogenic disease.

Secondary prevention centers on early recognition: test siblings for familial variants; screen genetically affected children for fasting hypoglycemia/HH, thyroid dysfunction, hearing loss, neuropathy, retinal disease, and emerging diabetes. The 2024 authors explicitly concluded that clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 in congenital hyperinsulinism. (welters2024congenitalhyperinsulinismin pages 1-2)

Tertiary prevention includes preventing hypoglycemic brain injury, optimizing glycemia to reduce conventional diabetic complications, treating hypothyroidism and hearing loss promptly, and rehabilitation to prevent falls and contractures. Vaccination has no disease-specific preventive role beyond routine diabetes and general-health recommendations.

14. Other species and natural disease

No well-established naturally occurring veterinary equivalent or zoonotic disease was identified. The disorder is genetic and not transmissible between species.

Orthologous Dnajc3/P58IPK genes are conserved in laboratory mammals and other vertebrates, reflecting conservation of ER proteostasis. Taxonomy suggestions for experimental evidence are Mus musculus (NCBI Taxon 10090) and, for referenced beta-cell experiments, Rattus norvegicus (Taxon 10116) and Homo sapiens (Taxon 9606). Exact ortholog NCBI Gene identifiers should be imported from NCBI rather than inferred from the articles.

15. Model organisms and experimental systems

Mouse model

The principal disease model is the Dnajc3/P58IPK knockout mouse, including the C57BL/6-Dnajc3tm8663Wcl line available through MMRRC. Mature knockouts develop beta-cell apoptosis, reduced beta-cell mass, hypoinsulinemia and progressive hyperglycemia, recapitulating the human diabetic mechanism. (welters2024congenitalhyperinsulinismin pages 7-9, welters2024congenitalhyperinsulinismin pages 9-10)

In the 2024 study, isolated islets from 3–8-week-old knockouts released more insulin during high-glucose stimulation, while islet insulin content was already significantly reduced by three weeks. Four-week-old mice had decreased basal and stimulated plasma insulin and impaired glucose tolerance, but no fasting- or challenge-associated hypoglycemia. Thus, mice reproduce beta-cell failure well but do not fully reproduce the prolonged human HH phase. (welters2024congenitalhyperinsulinismin pages 9-10)

Cellular systems

Patient-derived dermal fibroblasts: useful for proteomics, cholesterol stress, ER–Golgi, APP and mitochondrial/OXPHOS studies. Limitation: not a secretory beta cell or neuron. (jennings2021intracellularlipidaccumulation pages 1-2)
INS-1E cells and primary rat beta cells: model ER stress, insulin secretion and apoptosis.
Human islets: strongest ex-vivo beta-cell relevance; DNAJC3 loss/silencing has been associated with beta-cell apoptosis, although available material is limited. (welters2024congenitalhyperinsulinismin pages 1-2)
Retinal neurons: support vulnerability of neural sensory cells to DNAJC3 loss. (welters2024congenitalhyperinsulinismin pages 1-2)

No validated disease-specific zebrafish, Drosophila, C. elegans, organoid, humanized-knock-in, or patient-iPSC neuronal/beta-cell model was established in the retrieved literature. Developing isogenic CRISPR-corrected patient iPSC beta cells, cerebellar neurons, peripheral neurons and retinal organoids is a major research opportunity.

Recent development and evidence assessment

The key 2023–2024 advance is the 20 January 2024 human-plus-mouse study, which showed that HH may dominate through adolescence and proposed defective DNAJC3/BiP gating of Sec61 as the link between ER proteostasis and inappropriate intracellular calcium-triggered insulin secretion. Its abstract states: “HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence.” DOI: https://doi.org/10.3390/ijms25021270. (welters2024congenitalhyperinsulinismin pages 1-2)

The strongest disease-specific omics study remains Jennings et al., published 6 October 2021, DOI: https://doi.org/10.3389/fcell.2021.710247. Its patient-fibroblast proteomics connects ER stress to lipid accumulation, APP/amyloid processing, and mitochondrial bioenergetic failure. (jennings2021intracellularlipidaccumulation pages 1-2)

Important clinical expansions are Alwatban et al., September 2021, DOI: https://doi.org/10.3389/fendo.2021.742278, documenting pancreatic atrophy and major intrafamilial variability; and Ocansey et al., published online October 2021/in the 2022 volume, DOI: https://doi.org/10.1097/MCD.0000000000000397, confirming congenital HH and adding possible neutropenia and retinal manifestations. (alwatban2021casereporthomozygous pages 4-5, ocansey2022biallelicdnajc3variants pages 1-2, ocansey2022biallelicdnajc3variants pages 2-3)

Knowledge-base cautions and research priorities

Do not calculate phenotype percentages from the published cases as though they were a registry cohort.
Record HH and diabetes as potentially sequential—not mutually exclusive—phenotypes.
Distinguish the demonstrated ER-stress/beta-cell-apoptosis mechanism from the still-to-be-directly-confirmed Sec61/Ca²⁺ hypothesis.
Treat neutropenia, pituitary hypoplasia, retinal coloboma and some dysmorphic findings as provisional/variable extensions.
Revalidate OMIM, MONDO, Orphanet, HGNC, HPO, GO, CL, UBERON and NCIT numeric identifiers against their live releases before ingestion.
Highest-priority studies are a multicenter natural-history registry, systematic variant curation, standardized endocrine and neurologic surveillance, target-tissue iPSC models, direct calcium imaging, and therapeutic testing of proteostasis/ER-stress interventions.

PMID note: DOI and publication dates are supplied where established by the retrieved full texts. PubMed identifiers were not exposed in those source records and have therefore not been guessed; they should be resolved programmatically through Crossref/PubMed during database ingestion.

References

(welters2024congenitalhyperinsulinismin pages 1-2): Alena Welters, Oliver Nortmann, Laura Wörmeyer, Clemens Freiberg, Daniel Eberhard, Nadine Bachmann, Carsten Bergmann, Ertan Mayatepek, Thomas Meissner, and Sebastian Kummer. Congenital hyperinsulinism in humans and insulin secretory dysfunction in mice caused by biallelic dnajc3 variants. International Journal of Molecular Sciences, 25:1270, Jan 2024. URL: https://doi.org/10.3390/ijms25021270, doi:10.3390/ijms25021270. This article has 1 citations.
(ocansey2022biallelicdnajc3variants pages 4-6): Sharon Ocansey, Debbie Pullen, Patricia Atkinson, Antonia Clarke, Medard Hadonou, Charlene Crosby, John Short, Ian Christopher Lloyd, Damian Smedley, Albanese Assunta, Pratik Shah, and Meriel McEntagart. Biallelic dnajc3 variants in a neuroendocrine developmental disorder with insulin dysregulation. Clinical Dysmorphology, 31:11-17, Oct 2022. URL: https://doi.org/10.1097/mcd.0000000000000397, doi:10.1097/mcd.0000000000000397. This article has 8 citations and is from a peer-reviewed journal.
(alwatban2021casereporthomozygous pages 4-5): Saud Alwatban, Haifa Alfaraidi, Abdulaziz Alosaimi, Iram Alluhaydan, Majid Alfadhel, Michel Polak, and Angham Almutair. Case report: homozygous dnajc3 mutation causes monogenic diabetes mellitus associated with pancreatic atrophy. Frontiers in Endocrinology, Sep 2021. URL: https://doi.org/10.3389/fendo.2021.742278, doi:10.3389/fendo.2021.742278. This article has 10 citations.
(alwatban2021casereporthomozygous pages 1-2): Saud Alwatban, Haifa Alfaraidi, Abdulaziz Alosaimi, Iram Alluhaydan, Majid Alfadhel, Michel Polak, and Angham Almutair. Case report: homozygous dnajc3 mutation causes monogenic diabetes mellitus associated with pancreatic atrophy. Frontiers in Endocrinology, Sep 2021. URL: https://doi.org/10.3389/fendo.2021.742278, doi:10.3389/fendo.2021.742278. This article has 10 citations.
(ocansey2022biallelicdnajc3variants pages 1-2): Sharon Ocansey, Debbie Pullen, Patricia Atkinson, Antonia Clarke, Medard Hadonou, Charlene Crosby, John Short, Ian Christopher Lloyd, Damian Smedley, Albanese Assunta, Pratik Shah, and Meriel McEntagart. Biallelic dnajc3 variants in a neuroendocrine developmental disorder with insulin dysregulation. Clinical Dysmorphology, 31:11-17, Oct 2022. URL: https://doi.org/10.1097/mcd.0000000000000397, doi:10.1097/mcd.0000000000000397. This article has 8 citations and is from a peer-reviewed journal.
(ocansey2022biallelicdnajc3variants pages 2-3): Sharon Ocansey, Debbie Pullen, Patricia Atkinson, Antonia Clarke, Medard Hadonou, Charlene Crosby, John Short, Ian Christopher Lloyd, Damian Smedley, Albanese Assunta, Pratik Shah, and Meriel McEntagart. Biallelic dnajc3 variants in a neuroendocrine developmental disorder with insulin dysregulation. Clinical Dysmorphology, 31:11-17, Oct 2022. URL: https://doi.org/10.1097/mcd.0000000000000397, doi:10.1097/mcd.0000000000000397. This article has 8 citations and is from a peer-reviewed journal.
(welters2024congenitalhyperinsulinismin pages 2-3): Alena Welters, Oliver Nortmann, Laura Wörmeyer, Clemens Freiberg, Daniel Eberhard, Nadine Bachmann, Carsten Bergmann, Ertan Mayatepek, Thomas Meissner, and Sebastian Kummer. Congenital hyperinsulinism in humans and insulin secretory dysfunction in mice caused by biallelic dnajc3 variants. International Journal of Molecular Sciences, 25:1270, Jan 2024. URL: https://doi.org/10.3390/ijms25021270, doi:10.3390/ijms25021270. This article has 1 citations.
(welters2024congenitalhyperinsulinismin pages 9-10): Alena Welters, Oliver Nortmann, Laura Wörmeyer, Clemens Freiberg, Daniel Eberhard, Nadine Bachmann, Carsten Bergmann, Ertan Mayatepek, Thomas Meissner, and Sebastian Kummer. Congenital hyperinsulinism in humans and insulin secretory dysfunction in mice caused by biallelic dnajc3 variants. International Journal of Molecular Sciences, 25:1270, Jan 2024. URL: https://doi.org/10.3390/ijms25021270, doi:10.3390/ijms25021270. This article has 1 citations.
(ocansey2022biallelicdnajc3variants pages 3-4): Sharon Ocansey, Debbie Pullen, Patricia Atkinson, Antonia Clarke, Medard Hadonou, Charlene Crosby, John Short, Ian Christopher Lloyd, Damian Smedley, Albanese Assunta, Pratik Shah, and Meriel McEntagart. Biallelic dnajc3 variants in a neuroendocrine developmental disorder with insulin dysregulation. Clinical Dysmorphology, 31:11-17, Oct 2022. URL: https://doi.org/10.1097/mcd.0000000000000397, doi:10.1097/mcd.0000000000000397. This article has 8 citations and is from a peer-reviewed journal.
(ocansey2022biallelicdnajc3variants pages 6-7): Sharon Ocansey, Debbie Pullen, Patricia Atkinson, Antonia Clarke, Medard Hadonou, Charlene Crosby, John Short, Ian Christopher Lloyd, Damian Smedley, Albanese Assunta, Pratik Shah, and Meriel McEntagart. Biallelic dnajc3 variants in a neuroendocrine developmental disorder with insulin dysregulation. Clinical Dysmorphology, 31:11-17, Oct 2022. URL: https://doi.org/10.1097/mcd.0000000000000397, doi:10.1097/mcd.0000000000000397. This article has 8 citations and is from a peer-reviewed journal.
(alwatban2021casereporthomozygous pages 7-8): Saud Alwatban, Haifa Alfaraidi, Abdulaziz Alosaimi, Iram Alluhaydan, Majid Alfadhel, Michel Polak, and Angham Almutair. Case report: homozygous dnajc3 mutation causes monogenic diabetes mellitus associated with pancreatic atrophy. Frontiers in Endocrinology, Sep 2021. URL: https://doi.org/10.3389/fendo.2021.742278, doi:10.3389/fendo.2021.742278. This article has 10 citations.
(jennings2021intracellularlipidaccumulation pages 1-2): Matthew J. Jennings, Denisa Hathazi, Chi D. L. Nguyen, Benjamin Munro, Ute Münchberg, Robert Ahrends, Annette Schenck, Ilse Eidhof, Erik Freier, Matthis Synofzik, Rita Horvath, and Andreas Roos. Intracellular lipid accumulation and mitochondrial dysfunction accompanies endoplasmic reticulum stress caused by loss of the co-chaperone dnajc3. Frontiers in Cell and Developmental Biology, Oct 2021. URL: https://doi.org/10.3389/fcell.2021.710247, doi:10.3389/fcell.2021.710247. This article has 28 citations.
(welters2024congenitalhyperinsulinismin pages 7-9): Alena Welters, Oliver Nortmann, Laura Wörmeyer, Clemens Freiberg, Daniel Eberhard, Nadine Bachmann, Carsten Bergmann, Ertan Mayatepek, Thomas Meissner, and Sebastian Kummer. Congenital hyperinsulinism in humans and insulin secretory dysfunction in mice caused by biallelic dnajc3 variants. International Journal of Molecular Sciences, 25:1270, Jan 2024. URL: https://doi.org/10.3390/ijms25021270, doi:10.3390/ijms25021270. This article has 1 citations.
(synofzik2015absenceofbip pages 1-1): Matthis Synofzik, Tobias B. Haack, Robert Kopajtich, Matteo Gorza, Doron Rapaport, Markus Greiner, Caroline Schönfeld, Clemens Freiberg, Stefan Schorr, Reinhard W. Holl, Michael A. Gonzalez, Andreas Fritsche, Petra Fallier-Becker, Richard Zimmermann, Tim M. Strom, Thomas Meitinger, Stephan Züchner, Rebecca Schüle, Ludger Schöls, and Holger Prokisch. Absence of bip co-chaperone dnajc3 causes diabetes mellitus and multisystemic neurodegeneration. The American Journal of Human Genetics, 96:514, Mar 2015. URL: https://doi.org/10.1016/j.ajhg.2015.02.003, doi:10.1016/j.ajhg.2015.02.003. This article has 146 citations.
(alwatban2021casereporthomozygous pages 6-7): Saud Alwatban, Haifa Alfaraidi, Abdulaziz Alosaimi, Iram Alluhaydan, Majid Alfadhel, Michel Polak, and Angham Almutair. Case report: homozygous dnajc3 mutation causes monogenic diabetes mellitus associated with pancreatic atrophy. Frontiers in Endocrinology, Sep 2021. URL: https://doi.org/10.3389/fendo.2021.742278, doi:10.3389/fendo.2021.742278. This article has 10 citations.

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Juvenile-Onset Diabetes Mellitus With Central and Peripheral Neurodegeneration

Executive summary

1. Disease information

Definition and nomenclature

2. Etiology, risk, and protective factors

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3. Phenotypes

4. Genetic and molecular information

5. Environmental information

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