Retinitis pigmentosa 59 (RP59, DHDDS-related retinal degeneration) is an autosomal recessive rod-cone dystrophy caused by biallelic hypomorphic variants in DHDDS, which encodes the catalytic subunit of the cis-prenyltransferase complex that, together with NgBR (NUS1), synthesizes the polyprenyl backbone of dolichol, the lipid carrier for protein N-glycosylation. Almost all reported patients carry the founder missense variant c.124A>G (p.Lys42Glu, K42E), homozygously or in trans with p.Thr206Ala or another allele; the variant is concentrated in the Ashkenazi Jewish population, where DHDDS is one of the two commonest causes of recessive RP. Symptoms of night blindness and peripheral field loss typically begin in the second decade, electroretinographic responses are usually nondetectable by the time patients are examined, and macular involvement and loss of central photoreceptors occur earlier than in other common recessive forms. Patients show a characteristic shift of plasma and urinary dolichols toward shorter chain lengths (dolichol-18 replacing dolichol-19 as the dominant species), while serum transferrin glycosylation is generally normal, so the disease is usually non-syndromic despite the ubiquitous requirement for dolichol. How a partial loss of cis-prenyltransferase activity produces retina-restricted degeneration is unresolved: rod-specific Dhdds ablation and K42E knock-in mice degenerate or become dysfunctional without detectable loss of retinal protein N-glycosylation, and knock-in mice point to an inner-retinal synaptic defect rather than primary photoreceptor loss. A single adult K42E homozygote with a late-onset multisystem type 1 congenital disorder of glycosylation phenotype has been reported. No disease-specific therapy exists.
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name: Retinitis Pigmentosa 59
creation_date: "2026-09-30T19:45:00Z"
category: Mendelian
disease_term:
preferred_term: retinitis pigmentosa 59
term:
id: MONDO:0013468
label: retinitis pigmentosa 59
description: >-
Retinitis pigmentosa 59 (RP59, DHDDS-related retinal degeneration) is an
autosomal recessive rod-cone dystrophy caused by biallelic hypomorphic
variants in DHDDS, which encodes the catalytic subunit of the
cis-prenyltransferase complex that, together with NgBR (NUS1), synthesizes
the polyprenyl backbone of dolichol, the lipid carrier for protein
N-glycosylation. Almost all reported patients carry the founder missense
variant c.124A>G (p.Lys42Glu, K42E), homozygously or in trans with p.Thr206Ala
or another allele; the variant is concentrated in the Ashkenazi Jewish
population, where DHDDS is one of the two commonest causes of recessive RP.
Symptoms of night blindness and peripheral field loss typically begin in the
second decade, electroretinographic responses are usually nondetectable by the
time patients are examined, and macular involvement and loss of central
photoreceptors occur earlier than in other common recessive forms. Patients
show a characteristic shift of plasma and urinary dolichols toward shorter
chain lengths (dolichol-18 replacing dolichol-19 as the dominant species),
while serum transferrin glycosylation is generally normal, so the disease is
usually non-syndromic despite the ubiquitous requirement for dolichol. How a
partial loss of cis-prenyltransferase activity produces retina-restricted
degeneration is unresolved: rod-specific Dhdds ablation and K42E knock-in
mice degenerate or become dysfunctional without detectable loss of retinal
protein N-glycosylation, and knock-in mice point to an inner-retinal synaptic
defect rather than primary photoreceptor loss. A single adult K42E homozygote
with a late-onset multisystem type 1 congenital disorder of glycosylation
phenotype has been reported. No disease-specific therapy exists.
synonyms:
- RP59
- retinitis pigmentosa type 59
- DHDDS retinitis pigmentosa
- retinitis pigmentosa caused by mutation in DHDDS
- congenital disorder of glycosylation, type Ibb
- congenital disorder of glycosylation, type 1bb
- DHDDS-related inherited retinal degeneration
parents:
- Retinitis pigmentosa
- Inherited Retinal Dystrophy
references:
- reference: PMID:20301590
title: Nonsyndromic Retinitis Pigmentosa Overview.
tags:
- GeneReviews
notes: >-
Scope. This entry covers the recessive, retina-predominant disease caused by
biallelic DHDDS variants (MONDO:0013468, the OMIM RP59 / CDG1BB record). MONDO
places it under both retinitis pigmentosa and DHDDS-CDG (MONDO:1040054). The
fatal infantile multisystem type I CDG reported in one child compound
heterozygous for a DHDDS nonsense and a splice-site variant (PMID:27343064)
belongs to the broader DHDDS-CDG concept rather than to RP59 and is not
curated here. The dominant de novo DHDDS disorder with developmental delay,
seizures, myoclonus and later neurodegeneration (PMID:34382076) is a distinct
MONDO disease and is also out of scope; in this knowledge base DHDDS is
otherwise mentioned only as a gene in a developmental and epileptic
encephalopathy discovery series inside
Autosomal_Dominant_Non-Syndromic_Intellectual_Disability. ClinGen's Retina
Gene Curation Expert Panel classifies DHDDS as Definitive for DHDDS-CDG
(MONDO:1040054, autosomal recessive); because that assertion is made against
the broader MONDO concept rather than this entry's disease term, it is not
recorded under gene_disease_validity. The entry is a member of the
Retinitis Pigmentosa grouping but not of the Congenital Disorders of
Glycosylation grouping, whose necessary criterion is a defect that perturbs
protein N-glycosylation: transferrin glycosylation is normal in almost all
RP59 patients and retinal N-glycosylation is preserved in both mouse
models, so the N-glycosylation nodes here are recorded as hypothetical or
single-case. A DHDDS-CDG entry for the multisystem biallelic disease would
be the natural member of that grouping. GeneReviews has no DHDDS-specific
chapter; the Nonsyndromic Retinitis Pigmentosa Overview (PMID:20301590) covers
RP generally, and its PubMed record holds only the overview's statement of
purpose, so it supplies no DHDDS-specific phenotype baseline. Mouse retinas
lack a cone-rich macula, which limits how well knock-in models can test the
early macular involvement seen in patients. The phase III NAC Attack trial of
N-acetylcysteine (PMID:39864434) addresses retinitis pigmentosa in general
rather than RP59, so it is not curated as a treatment here.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Disease requires biallelic DHDDS variants. The founder K42E allele was
identified homozygously by homozygosity mapping in Ashkenazi Jewish families
with autosomal recessive RP; compound heterozygotes K42E/T206A and K42E/R98W
have also been reported. Heterozygous carriers are unaffected but show an
intermediate shift in dolichol chain length.
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Sequence analysis revealed a founder homozygous missense mutation,
c.124A>G (p.Lys42Glu), in the dehydrodolichyl diphosphate synthase gene
(DHDDS) in 20 AJ patients with RP of 15 unrelated families.
explanation: >-
Homozygosity mapping and sequencing in 15 families establish recessive
inheritance of the founder K42E allele.
- reference: PMID:24078709
reference_title: "Aberrant dolichol chain lengths as biomarkers for retinitis pigmentosa caused by impaired dolichol biosynthesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
K42E/K42E and K42E/T206A patients have significantly higher plasma and
urinary D18/D19 ratios than K42E and T206A carriers.
explanation: >-
Documents homozygous and compound heterozygous affected genotypes and
separates them biochemically from heterozygous carriers.
prevalence:
- population: Ashkenazi Jewish (ethnically matched controls, Israel)
measure_type: CARRIER_FREQUENCY
prevalence_class: ABOVE_1_IN_1000
rate_per_100000: 310.6
notes: >-
K42E carrier frequency of 1 in 322 ethnically matched Ashkenazi Jewish
control individuals (100000/322). A single observed carrier, so the
estimate is imprecise.
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mutation was found heterozygously in 1 out of 322 ethnically matched
normal control individuals.
explanation: Direct count of K42E carriers among Ashkenazi Jewish controls.
- population: General population (all ancestries)
measure_type: UNKNOWN
prevalence_class: RARE
notes: >-
No population prevalence estimate has been published. Outside the Ashkenazi
Jewish population the disease is rare; within it, DHDDS accounts for
roughly one third of genetically solved recessive RP.
evidence:
- reference: PMID:36362109
reference_title: "Vertebrate Animal Models of RP59: Current Status and Future Prospects."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
While the frequency of RP59 is rare in the general population, it has
been estimated RP59 accounts for nearly one-third of RP cases involving
Ashkenazi Jewish patients.
explanation: Review statement of overall rarity with enrichment in Ashkenazi Jews.
- reference: PMID:21295283
reference_title: "Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The identified Lys42Glu variant likely arose from an ancestral founder,
because eight of the nine identified alleles in 27,174 control
chromosomes were of confirmed Ashkenazi Jewish ethnicity.
explanation: >-
The K42E allele is very rare in unselected control chromosomes and is
largely confined to Ashkenazi Jewish ancestry.
genetic:
- name: DHDDS
gene_term:
preferred_term: DHDDS
term:
id: hgnc:20603
label: DHDDS
relationship_type: CAUSATIVE
association: Causative
variant_origin: GERMLINE
features: >-
Biallelic hypomorphic missense variants. The founder c.124A>G (p.Lys42Glu)
lies near the active site and lowers catalytic efficiency; p.Thr206Ala has
been found only in trans with K42E in patients, and its pathogenicity is
supported by the dolichol profile of K42E/T206A patients and by knock-in
mice. p.Arg98Trp has been reported in trans with K42E in a single patient.
case_fractions:
- population: Ashkenazi Jewish families with RP and a known genetic cause (Israel)
case_fraction_percent: 33.0
notes: >-
Share of genetically solved families in a cohort of 230 Ashkenazi Jewish
RP families, of which 37% were solved; DHDDS K42E was second only to the
MAK Alu insertion.
evidence:
- reference: PMID:29276052
reference_title: "Nonsyndromic Retinitis Pigmentosa in the Ashkenazi Jewish Population: Genetic and Clinical Aspects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most prevalent RP-causing mutations are the Alu insertion
(c.1297_8ins353, p.K433Rins31*) in the male germ cell-associated kinase
(MAK) gene (39% of families with a known genetic cause for RP) and
c.124A>G, p.K42E in dehydrodolichol diphosphate synthase (DHDDS) (33%).
explanation: Quantifies the DHDDS K42E share among solved Ashkenazi Jewish RP families.
- population: North American recessive or isolate RP patients reporting Jewish ancestry
case_fraction_percent: 8.6
cohort_size: 35
evidence:
- reference: PMID:25255364
reference_title: "Two specific mutations are prevalent causes of recessive retinitis pigmentosa in North American patients of Jewish ancestry."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified the MAK and DHDDS mutations homozygously in only 2.1% and
0.8%, respectively, of patients of mixed ethnicity, but in 25.7% and
8.6%, respectively, of cases reporting Jewish ancestry.
explanation: Homozygous K42E accounts for 8.6% of Jewish-ancestry cases screened.
- population: North American recessive or isolate RP patients of mixed ethnicity
case_fraction_percent: 0.8
cohort_size: 240
evidence:
- reference: PMID:25255364
reference_title: "Two specific mutations are prevalent causes of recessive retinitis pigmentosa in North American patients of Jewish ancestry."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified the MAK and DHDDS mutations homozygously in only 2.1% and
0.8%, respectively, of patients of mixed ethnicity, but in 25.7% and
8.6%, respectively, of cases reporting Jewish ancestry.
explanation: Homozygous K42E is uncommon outside Jewish-ancestry patients.
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Sequence analysis revealed a founder homozygous missense mutation,
c.124A>G (p.Lys42Glu), in the dehydrodolichyl diphosphate synthase gene
(DHDDS) in 20 AJ patients with RP of 15 unrelated families.
explanation: Discovery of DHDDS as the RP59 gene in Ashkenazi Jewish families.
- reference: PMID:21295283
reference_title: "Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a single, one-generation, nonsyndromic RP family, we have identified a
gene, dehydrodolichol diphosphate synthase (DHDDS), demonstrating the
power of combining whole-exome sequencing with rapid in vivo studies.
explanation: Independent co-discovery of DHDDS by exome sequencing.
- reference: PMID:28130426
reference_title: "Genetic analysis of 10 pedigrees with inherited retinal degeneration by exome sequencing and phenotype-genotype association."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The DHDDS gene was screened for mutations in the remaining two pedigrees
with Ashkenazi Jewish ancestry.
explanation: >-
Targeted DHDDS screening in Ashkenazi Jewish pedigrees, which identified
K42E and the then-novel T206A allele.
- reference: PMID:24078709
reference_title: "Aberrant dolichol chain lengths as biomarkers for retinitis pigmentosa caused by impaired dolichol biosynthesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Dolichol analysis also provides evidence that the T206A mutation is RP-causative.
explanation: Biochemical support for T206A as a second pathogenic allele.
- name: ALG6 F304S modifier variant
gene_term:
preferred_term: ALG6
term:
id: hgnc:23157
label: ALG6
relationship_type: MODIFIER
features: >-
The common ALG6 p.Phe304Ser polymorphism, which does not itself cause CDG,
was associated with a shift in retinal disease distribution among K42E
homozygotes: more severe macular cone disease with milder peripheral rod
disease. Based on 11 patients.
evidence:
- reference: PMID:38256083
reference_title: "Inherited Retinal Degeneration Caused by Dehydrodolichyl Diphosphate Synthase Mutation-Effect of an ALG6 Modifier Variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The ALG6 variant, (F304S), was correlated with greater macular cone
disease severity and less peripheral rod disease severity.
explanation: Candidate modifier association in a small K42E patient series.
mechanistic_hypotheses:
- hypothesis_group_id: cdg_hypoglycosylation_model
hypothesis_label: Photoreceptor protein hypoglycosylation (RP59 as a congenital disorder of glycosylation)
status: ALTERNATIVE
description: >-
The original model: reduced cis-prenyltransferase activity limits
dolichol-linked oligosaccharide supply, rhodopsin and other photoreceptor
glycoproteins are underglycosylated, and rods degenerate as in
rhodopsin glycosylation-site mutants. Zebrafish knockdown supports it, but
normal transferrin glycosylation in patients and preserved retinal
N-glycosylation in both rod-specific knockout and K42E knock-in mice argue
against it as the primary retinal mechanism.
evidence:
- reference: PMID:21295283
reference_title: "Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Zebrafish studies showed virtually identical photoreceptor defects as
observed with N-linked glycosylation-interfering mutations in the
light-sensing protein rhodopsin.
explanation: Phenocopy of glycosylation-defective rhodopsin in dhdds morphant zebrafish.
- reference: PMID:32526701
reference_title: "Retinal Degeneration Caused by Rod-Specific Dhdds Ablation Occurs without Concomitant Inhibition of Protein N-Glycosylation."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: >-
These findings challenge the conventional mechanistic view of RP59 as a
congenital disorder of glycosylation.
explanation: Rod degeneration occurred with retinal N-glycosylation preserved.
- hypothesis_group_id: glycosylation_independent_dolichol_model
hypothesis_label: Glycosylation-independent photoreceptor dolichol deficit
status: EMERGING
description: >-
Reduced or chain-shortened dolichol in photoreceptors damages them through a
route other than bulk N-glycosylation, for example by destabilizing the
outer-segment disc membranes in which dolichol is thought to influence
fluidity and fusion.
evidence:
- reference: PMID:24664694
reference_title: "Mutation K42E in dehydrodolichol diphosphate synthase (DHDDS) causes recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we believe that the mutation may lead to low dolichol levels in
photoreceptor outer segments, resulting in unstable membrane structure
that leads to photoreceptor degeneration.
explanation: Authors' proposed membrane mechanism, stated as a hypothesis.
- reference: PMID:32526701
reference_title: "Retinal Degeneration Caused by Rod-Specific Dhdds Ablation Occurs without Concomitant Inhibition of Protein N-Glycosylation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Retina dolichol levels were markedly decreased by PN 4 weeks in
Dhddsflx/flx iCre+ mice, relative to controls; despite this,
N-glycosylation of retinal proteins, including opsin (the dominant
rod-specific glycoprotein), persisted in Dhddsflx/flx iCre+ mice.
explanation: Dolichol loss and degeneration without detectable hypoglycosylation.
- hypothesis_group_id: inner_retina_synaptic_model
hypothesis_label: Photoreceptor-to-bipolar synaptic transmission defect
status: EMERGING
description: >-
In K42E and T206A knock-in mice the earliest and dominant defect is a
reduced ERG b-wave with preserved a-wave, inner nuclear layer thinning and
loss of bipolar and amacrine cells, suggesting defective transmission from
photoreceptors to the inner retina. A corresponding human signature has not
been demonstrated, because most patients already have nondetectable ERGs.
evidence:
- reference: PMID:37443173
reference_title: "A Dhdds K42E knock-in RP59 mouse model shows inner retina pathology and defective synaptic transmission."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our results suggest that the underlying cause of DHDDS K42E variant
driven RP59 retinal pathology is defective synaptic transmission from
outer to inner retina.
explanation: Knock-in model conclusion that motivates this hypothesis.
- reference: PMID:40574710
reference_title: "Dhdds T206A and Dhdds K42E knock-in mouse models of retinitis pigmentosa 59 are phenotypically similar."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We propose that the physiological basis of retinal dysfunction in RP59
involves defective photoreceptor to bipolar cell synaptic transmission
with concomitant bipolar/amacrine cell degeneration.
explanation: Replicated with the second patient allele, T206A.
- hypothesis_group_id: rpe_contribution_model
hypothesis_label: Retinal pigment epithelium contribution
status: EMERGING
description: >-
Loss of DHDDS in the retinal pigment epithelium is sufficient to cause RPE
atrophy and secondary photoreceptor loss in mice, and patients show early
macular autofluorescence changes; whether RPE involvement is primary in
human RP59 is unresolved, and one patient histology showed relative RPE
preservation.
evidence:
- reference: PMID:32245241
reference_title: "Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These results indicate that RPE dysfunction contributes to DHDDS
mutation-mediated pathology and suggests a more complicated disease
mechanism than simply disruption of glycosylation.
explanation: RPE-specific Dhdds ablation produces retinal degeneration.
pathophysiology:
- name: DHDDS Cis-Prenyltransferase Partial Loss of Function
description: >-
DHDDS forms the catalytic subunit of the heterotetrameric
cis-prenyltransferase with the NgBR (NUS1) subunit, which condenses
isopentenyl diphosphate onto farnesyl diphosphate to build the polyprenyl
diphosphate backbone of dolichol. The RP59 K42E substitution destabilizes
the active site, raises the Km for farnesyl diphosphate and lowers kcat,
leaving substantial residual activity. DHDDS is expressed ubiquitously and
is concentrated in rod and cone inner segments in the human retina.
biological_scale: MOLECULAR
conforms_to: "photoreceptor_degeneration#Photoreceptor Gene Defect"
genes:
- preferred_term: DHDDS
term:
id: hgnc:20603
label: DHDDS
- preferred_term: NUS1 (NgBR)
term:
id: hgnc:21042
label: NUS1
genetic_context:
variant_origin: GERMLINE
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
description: >-
Biallelic missense variants (K42E homozygous; K42E/T206A; K42E/R98W).
molecular_functions:
- preferred_term: dehydrodolichyl diphosphate synthase activity
modifier: DECREASED
term:
id: GO:0045547
label: ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity
cellular_components:
- preferred_term: dehydrodolichyl diphosphate synthase complex
term:
id: GO:1904423
label: dehydrodolichyl diphosphate synthase complex
cell_types:
- preferred_term: rod photoreceptor cell
term:
id: CL:0000604
label: retinal rod cell
- preferred_term: cone photoreceptor cell
term:
id: CL:0000573
label: retinal cone cell
evidence:
- reference: PMID:24664694
reference_title: "Mutation K42E in dehydrodolichol diphosphate synthase (DHDDS) causes recessive retinitis pigmentosa."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: IN_VITRO
snippet: >-
The identified mutation changes the highly conserved residue Lys42 to
Glu, resulting in lower catalytic efficiency.
explanation: >-
K42E lowers DHDDS catalytic efficiency. The quoted sentence states an
enzyme property that this family report does not itself measure, so it
is graded by the enzymology it describes; the measured kinetics are in
the PMID:32817466 item below.
- reference: PMID:32817466
reference_title: "Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: IN_VITRO
snippet: >-
this interpretation is consistent with the observation that K42E
mutation increases the KM for FPP, decreases kcat, but has no effect on
IPP binding
explanation: Kinetic basis of the partial loss of function.
- reference: PMID:33077723
reference_title: "Structural basis of heterotetrameric assembly and disease mutations in the human cis-prenyltransferase complex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Here, we reveal that hcis-PT exhibits a heterotetrameric assembly in
solution, consisting of two catalytic dehydrodolichyl diphosphate
synthase (DHDDS) and inactive Nogo-B receptor (NgBR) heterodimers.
explanation: Defines DHDDS as the catalytic subunit of the complex with NgBR.
- reference: PMID:33077723
reference_title: "Structural basis of heterotetrameric assembly and disease mutations in the human cis-prenyltransferase complex."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
We noticed that within the timeframe of the simulations, the K42E
mutation results in active-site destabilization, including the
C-terminus of NgBR
explanation: Molecular dynamics model of how K42E perturbs the active site.
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Immunohistochemical analysis of the human retina with anti-DHDDS
antibodies revealed intense labeling of the cone and rod photoreceptor
inner segments.
explanation: DHDDS protein is concentrated in photoreceptor inner segments.
downstream:
- target: Dolichol Chain-Length Shortening
causal_link_type: DIRECT
evidence:
- reference: PMID:32817466
reference_title: "Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: IN_VITRO
snippet: K42E also causes product chain shortening (25, 49), which will be discussed below.
explanation: The mutant enzyme makes shorter polyprenyl products.
- name: Dolichol Chain-Length Shortening
description: >-
The mutant enzyme shifts the dolichol pool toward shorter isoprenologues.
In patients dolichol-18 replaces dolichol-19 as the dominant species in
plasma and urine, and carriers show an intermediate shift; K42E knock-in
mice show the same shortening in retina, liver and brain.
biological_scale: MOLECULAR
chemical_entities:
- preferred_term: dolichol
modifier: ABNORMAL
term:
id: CHEBI:16091
label: dolichol
biological_processes:
- preferred_term: dolichyl diphosphate biosynthesis
modifier: ABNORMAL
term:
id: GO:0006489
label: dolichyl diphosphate biosynthetic process
evidence:
- reference: PMID:24078709
reference_title: "Aberrant dolichol chain lengths as biomarkers for retinitis pigmentosa caused by impaired dolichol biosynthesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dolichol-18 (D18) became the dominant dolichol species in patients
instead of dolichol-19 (D19) in normal individuals.
explanation: Chain-length shift in patient plasma and urine.
- reference: PMID:37443173
reference_title: "A Dhdds K42E knock-in RP59 mouse model shows inner retina pathology and defective synaptic transmission."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Here, we report that the Dol isoprenylogue species in retina, liver, and
brain of the K42E mouse model are statistically shorter than in the
corresponding tissues of age-matched controls, as reported in blood and
urine of RP59 patients.
explanation: The same shortening occurs in retina of the knock-in model.
downstream:
- target: Impaired Photoreceptor Protein N-Glycosylation
causal_link_type: UNKNOWN
hypothesis_groups:
- cdg_hypoglycosylation_model
- target: Rod Photoreceptor Degeneration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
hypothesis_groups:
- glycosylation_independent_dolichol_model
- target: Photoreceptor-to-Bipolar Cell Synaptic Transmission Defect
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
hypothesis_groups:
- inner_retina_synaptic_model
evidence:
- reference: PMID:37443173
reference_title: "A Dhdds K42E knock-in RP59 mouse model shows inner retina pathology and defective synaptic transmission."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Electroretinograms (ERGs) of mutant mice exhibited reduced b-wave
amplitudes beginning at PN 1-mo, progressively declining through PN
18-mo, without appreciable a-wave attenuation, relative to controls.
explanation: >-
In the same knock-in mice that carry the shortened dolichol profile,
the functional defect is a selective b-wave loss.
- target: Retinal Pigment Epithelium Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
hypothesis_groups:
- rpe_contribution_model
- target: Systemic Protein Hypoglycosylation
causal_link_type: UNKNOWN
hypothesis_groups:
- cdg_hypoglycosylation_model
- name: Impaired Photoreceptor Protein N-Glycosylation
description: >-
Proposed deficit in N-glycosylation of rhodopsin and other photoreceptor
glycoproteins from limiting dolichol supply. Direct tests have not found it:
patient transferrin glycosylation is normal, and neither rod-specific
Dhdds knockout nor K42E knock-in mouse retina shows loss of protein
N-glycosylation. The node is kept to record the contested model and the
evidence against it.
biological_scale: MOLECULAR
mechanism_confidence: HYPOTHETICAL
biological_processes:
- preferred_term: protein N-linked glycosylation
modifier: DECREASED
term:
id: GO:0006487
label: protein N-linked glycosylation
cell_types:
- preferred_term: rod photoreceptor cell
term:
id: CL:0000604
label: retinal rod cell
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DHDDS is a key enzyme in the pathway of dolichol, which plays an
important role in N-glycosylation of many glycoproteins, including
rhodopsin.
explanation: Rationale linking DHDDS to rhodopsin glycosylation.
- reference: PMID:24664694
reference_title: "Mutation K42E in dehydrodolichol diphosphate synthase (DHDDS) causes recessive retinitis pigmentosa."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
Patterns of plasma transferrin isoelectric focusing gel were normal in
all family members, indicating no significant abnormality in protein
glycosylation.
explanation: No systemic glycosylation defect in K42E homozygotes.
- reference: PMID:32272552
reference_title: "Lack of Overt Retinal Degeneration in a K42E Dhdds Knock-In Mouse Model of RP59."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: >-
Hence, retinas of DhddsK42E/K42E mice exhibited no overt signs of
degeneration, yet were markedly gliotic, but without evidence of
compromised protein N-glycosylation.
explanation: The patient allele does not reduce retinal N-glycosylation in mice.
- reference: PMID:32526701
reference_title: "Retinal Degeneration Caused by Rod-Specific Dhdds Ablation Occurs without Concomitant Inhibition of Protein N-Glycosylation."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: >-
Retina dolichol levels were markedly decreased by PN 4 weeks in
Dhddsflx/flx iCre+ mice, relative to controls; despite this,
N-glycosylation of retinal proteins, including opsin (the dominant
rod-specific glycoprotein), persisted in Dhddsflx/flx iCre+ mice.
explanation: Opsin remains glycosylated even after rod-specific Dhdds ablation.
downstream:
- target: Rod Photoreceptor Degeneration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
hypothesis_groups:
- cdg_hypoglycosylation_model
evidence:
- reference: PMID:21295283
reference_title: "Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Zebrafish studies showed virtually identical photoreceptor defects as
observed with N-linked glycosylation-interfering mutations in the
light-sensing protein rhodopsin.
explanation: >-
Phenocopy argument for the edge; it does not measure glycosylation in
the morphants.
- name: Rod Photoreceptor Degeneration
description: >-
Rod photoreceptors lose their outer segments and die, producing night
blindness and peripheral field loss. Rod-specific ablation of Dhdds causes
rapid loss of rods followed by cones, and dhdds knockdown in zebrafish
abolishes photoreceptor outer segments; in the human K42E disease rod
function is typically already lost when patients are first examined.
biological_scale: CELLULAR
conforms_to: "photoreceptor_degeneration#Rod Photoreceptor Apoptosis"
cell_types:
- preferred_term: rod photoreceptor cell
term:
id: CL:0000604
label: retinal rod cell
biological_processes:
- preferred_term: photoreceptor cell maintenance
modifier: DECREASED
term:
id: GO:0045494
label: photoreceptor cell maintenance
- preferred_term: photoreceptor outer segment organization
modifier: ABNORMAL
term:
id: GO:0035845
label: photoreceptor cell outer segment organization
- preferred_term: neuron apoptotic process
modifier: INCREASED
term:
id: GO:0051402
label: neuron apoptotic process
cellular_components:
- preferred_term: rod photoreceptor outer segment
modifier: ABNORMAL
term:
id: GO:0120200
label: rod photoreceptor outer segment
evidence:
- reference: PMID:32526701
reference_title: "Retinal Degeneration Caused by Rod-Specific Dhdds Ablation Occurs without Concomitant Inhibition of Protein N-Glycosylation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
rapid photoreceptor degeneration ensued, resulting in almost complete
loss of rods and cones by PN 6 weeks
explanation: Rod-specific Dhdds loss is sufficient for photoreceptor degeneration.
- reference: PMID:24664742
reference_title: "Knock-down DHDDS expression induces photoreceptor degeneration in zebrafish."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Morphological analysis showed that photoreceptor outer segments in
retinas of MO-injected fish are very short and in many cases completely
missing.
explanation: Outer segment loss after dhdds knockdown in zebrafish.
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Symptoms occurred during the latter part of the second decade of life in
all three siblings, and these related to decreasing night and side
vision; loss of reading (central) vision was not an early complaint.
explanation: Rod-first clinical course in K42E homozygotes.
- reference: PMID:32272552
reference_title: "Lack of Overt Retinal Degeneration in a K42E Dhdds Knock-In Mouse Model of RP59."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: >-
Retinas of DhddsK42E/K42E mice exhibited grossly normal histological
organization from 1 to 12 months of age.
explanation: >-
The knock-in mouse carrying the human allele does not show this node,
a species mismatch recorded in discussions.
downstream:
- target: Secondary Cone Degeneration and Outer Retinal Thinning
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Nyctalopia
causal_link_type: DIRECT
- target: Rod-cone dystrophy
causal_link_type: DIRECT
- name: Secondary Cone Degeneration and Outer Retinal Thinning
description: >-
Cone loss follows rod loss, with progressive thinning of the photoreceptor
layer that spares the fovea early but reaches it by the fourth decade.
Compared with MAK-related RP, cone ERGs become nondetectable at younger ages
and macular involvement is more marked.
biological_scale: TISSUE
conforms_to: "photoreceptor_degeneration#Secondary Cone Degeneration and Outer Retinal Thinning"
cell_types:
- preferred_term: cone photoreceptor cell
term:
id: CL:0000573
label: retinal cone cell
locations:
- preferred_term: macula
term:
id: UBERON:0000053
label: macula lutea
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
OCT imaging in early disease showed preserved central retinal
photoreceptors but a decline in photoreceptor layer thickness with
distance from the fovea
explanation: Centripetal outer retinal thinning.
- reference: PMID:29276052
reference_title: "Nonsyndromic Retinitis Pigmentosa in the Ashkenazi Jewish Population: Genetic and Clinical Aspects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with DHDDS mutations were referred for electrophysiologic
evaluation at earlier ages, and their cone responses became
nondetectable at a much younger age than MAK patients.
explanation: Early cone involvement in DHDDS disease.
downstream:
- target: Constriction of peripheral visual field
causal_link_type: DIRECT
- target: Reduced visual acuity
causal_link_type: DIRECT
- target: Photoreceptor layer loss on macular OCT
causal_link_type: DIRECT
- target: Undetectable electroretinogram
causal_link_type: DIRECT
- target: Spicular pigmentation of the retina
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Attenuation of retinal blood vessels
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Optic disc pallor
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Cystoid macular edema
causal_link_type: UNKNOWN
- name: Photoreceptor-to-Bipolar Cell Synaptic Transmission Defect
description: >-
In K42E/K42E, T206A/T206A and T206A/K42E knock-in mice the ERG b-wave falls
while the photoreceptor-driven a-wave is preserved, the outer plexiform
layer is disrupted and outer nuclear layer nuclei become ectopic,
indicating failed signalling from photoreceptors to second-order neurons.
Established only in mice.
biological_scale: CELLULAR
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: rod photoreceptor cell
term:
id: CL:0000604
label: retinal rod cell
- preferred_term: retinal bipolar neuron
term:
id: CL:0000748
label: retinal bipolar neuron
biological_processes:
- preferred_term: chemical synaptic transmission
modifier: DECREASED
term:
id: GO:0007268
label: chemical synaptic transmission
locations:
- preferred_term: outer plexiform layer of retina
term:
id: UBERON:0001790
label: outer plexiform layer of retina
evidence:
- reference: PMID:37443173
reference_title: "A Dhdds K42E knock-in RP59 mouse model shows inner retina pathology and defective synaptic transmission."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Histological analysis revealed cell loss in the INL, outer plexiform
layer (OPL) disruption, and ectopic localization of outer nuclear layer
(ONL) nuclei into the OPL of K42E mutant retinas, relative to controls.
explanation: Structural correlate of the synaptic defect in the knock-in model.
- reference: PMID:40574710
reference_title: "Dhdds T206A and Dhdds K42E knock-in mouse models of retinitis pigmentosa 59 are phenotypically similar."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Electroretinography (ERG) revealed a reduction in b-waves, but spared
reduction in a-wave amplitudes.
explanation: The same b-wave-selective defect with the T206A allele.
downstream:
- target: Inner Nuclear Layer Thinning with Bipolar and Amacrine Cell Loss
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
hypothesis_groups:
- inner_retina_synaptic_model
- name: Inner Nuclear Layer Thinning with Bipolar and Amacrine Cell Loss
description: >-
Progressive thinning of the inner nuclear layer and total retina from about
two months of age in knock-in mice, with reduced bipolar and amacrine cell
densities, while outer nuclear layer thickness is maintained to 12 months.
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: retinal bipolar neuron
term:
id: CL:0000748
label: retinal bipolar neuron
- preferred_term: amacrine cell
term:
id: CL:0000561
label: amacrine cell
locations:
- preferred_term: inner nuclear layer of retina
term:
id: UBERON:0001791
label: inner nuclear layer of retina
evidence:
- reference: PMID:40574710
reference_title: "Dhdds T206A and Dhdds K42E knock-in mouse models of retinitis pigmentosa 59 are phenotypically similar."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Consistent with a reduction in inner nuclear layer thickness as seen by
using optical coherence tomography (OCT), cell loss observed by
histology, as well as bipolar and amacrine cell densities were reduced
in all Dhdds mutant phenotypes compared to those of PN 8-12 mo
age-matched controls.
explanation: Inner retinal cell loss across K42E and T206A genotypes.
- name: Retinal Pigment Epithelium Dysfunction
description: >-
RPE-specific Dhdds ablation in mice causes RPE hyper-reflectivity,
transmigration of RPE cells into the photoreceptor layer and patchy
photoreceptor loss, and patients show early abnormal macular
autofluorescence; however, histology from one DHDDS patient found the RPE
relatively preserved amid severe retinal degeneration.
biological_scale: CELLULAR
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: retinal pigment epithelial cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
locations:
- preferred_term: retinal pigment epithelium
term:
id: UBERON:0001782
label: pigmented layer of retina
evidence:
- reference: PMID:32245241
reference_title: "Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
At three months, RPE and photoreceptor disruption was observed
non-uniformly across the retina as well as RPE transmigration into the
photoreceptor layer, external limiting membrane descent towards the RPE,
and patchy loss of photoreceptors.
explanation: RPE loss of Dhdds disrupts the RPE and overlying photoreceptors.
- reference: PMID:35501492
reference_title: "Ultra-widefield fundus autofluorescence imaging in patients with autosomal recessive retinitis pigmentosa reveals a genotype-phenotype correlation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Specifically, DHDDS patients had a more abnormal macular FAF pattern and
more widespread decrease in peripheral autofluorescence.
explanation: Autofluorescence abnormalities consistent with RPE involvement in patients.
- reference: PMID:28130426
reference_title: "Genetic analysis of 10 pedigrees with inherited retinal degeneration by exome sequencing and phenotype-genotype association."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
Retinal histopathology of a patient with a DHDDS mutation showed severe
degeneration of retinal layers with relative preservation of the retinal
pigment epithelium.
explanation: One patient's histology argues against primary RPE loss.
downstream:
- target: Rod Photoreceptor Degeneration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
hypothesis_groups:
- rpe_contribution_model
- target: Abnormal fundus autofluorescence imaging
causal_link_type: DIRECT
- name: Systemic Protein Hypoglycosylation
description: >-
Not a feature of typical RP59, in which transferrin glycosylation is
normal. A single adult K42E homozygote developed late-onset seizures,
ataxia, tremor, titubation and protein-losing enteropathy with an elevated
mono-oligo/di-oligo transferrin ratio (a type 1 CDG pattern), suggesting
that the same genotype can occasionally reach a systemic glycosylation
threshold, possibly through modifier effects.
biological_scale: MOLECULAR
mechanism_confidence: PROVISIONAL
conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
biological_processes:
- preferred_term: protein N-linked glycosylation
modifier: DECREASED
term:
id: GO:0006487
label: protein N-linked glycosylation
evidence:
- reference: PMID:36046393
reference_title: "Acetazolamide treatment in late onset CDG type 1 due to biallelic pathogenic DHDDS variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
An adult Ashkenazi Jewish female developed multiple symptoms of late
onset type 1 CDG including seizures, ataxia, protein losing enteropathy,
tremor, and titubation in association with elevated mono-oligo/di-oligo
transferrin ratio in blood, and classic retinitis pigmentosa.
explanation: Single-case evidence of systemic hypoglycosylation in a K42E homozygote.
- reference: PMID:38256083
reference_title: "Inherited Retinal Degeneration Caused by Dehydrodolichyl Diphosphate Synthase Mutation-Effect of an ALG6 Modifier Variant."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
Apart from a retinal phenotype, however, DHDDS-IRD is surprisingly
non-syndromic (i.e., without any systemic manifestations).
explanation: The usual disease course lacks systemic involvement.
downstream:
- target: Seizure
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Ataxia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Tremor
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Titubation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Protein-losing enteropathy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Nyctalopia
category: Ophthalmologic
frequency: VERY_FREQUENT
description: >-
Night blindness, usually the presenting symptom, beginning in the second
decade.
phenotype_term:
preferred_term: Nyctalopia
term:
id: HP:0000662
label: Nyctalopia
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most patients had symptoms of night and peripheral vision loss,
nondetectable electroretinographic responses, constriction of visual
fields, and funduscopic hallmarks of retinal degeneration.
explanation: Night vision loss in most K42E homozygotes.
- reference: PMID:38256083
reference_title: "Inherited Retinal Degeneration Caused by Dehydrodolichyl Diphosphate Synthase Mutation-Effect of an ALG6 Modifier Variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: P1 (Table 3) reported the onset of nyctalopia at age 18.
explanation: Onset of nyctalopia in late adolescence in a K42E patient.
- name: Rod-cone dystrophy
category: Ophthalmologic
description: Progressive rod-first photoreceptor degeneration (retinitis pigmentosa).
phenotype_term:
preferred_term: Rod-cone dystrophy
term:
id: HP:0000510
label: Rod-cone dystrophy
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical manifestations of patients who are homozygous for the c.124A>G
mutation were within the spectrum associated with arRP.
explanation: The disease presents as typical autosomal recessive RP.
- name: Constriction of peripheral visual field
category: Ophthalmologic
frequency: VERY_FREQUENT
description: Progressive concentric visual field loss.
phenotype_term:
preferred_term: Constriction of peripheral visual field
clinical_course: PROGRESSIVE
term:
id: HP:0001133
label: Constriction of peripheral visual field
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most patients had symptoms of night and peripheral vision loss,
nondetectable electroretinographic responses, constriction of visual
fields, and funduscopic hallmarks of retinal degeneration.
explanation: Visual field constriction in most patients.
- name: Undetectable electroretinogram
category: Ophthalmologic
frequency: VERY_FREQUENT
description: >-
Rod and cone full-field ERGs are nondetectable or severely attenuated in
most patients when first recorded.
phenotype_term:
preferred_term: Undetectable electroretinogram
term:
id: HP:0000550
label: Undetectable electroretinogram
evidence:
- reference: PMID:38256083
reference_title: "Inherited Retinal Degeneration Caused by Dehydrodolichyl Diphosphate Synthase Mutation-Effect of an ALG6 Modifier Variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Specifically, 10 of 11 patients had recordings performed at ages varying
from 17 to 56 years and both rod and cone ERGs were either not detectable
or severely attenuated.
explanation: Nondetectable or severely attenuated ERGs across a K42E series.
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ERG responses were nondetectable in most patients (Table S2).
explanation: Nondetectable ERGs in the discovery cohort.
- name: Spicular pigmentation of the retina
category: Ophthalmologic
description: Bone spicule-like pigment migration in the mid-periphery.
phenotype_term:
preferred_term: Bone spicule pigmentation of the retina
term:
id: HP:0007737
label: Spicular pigmentation of the retina
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Funduscopic findings at various disease stages included waxy appearance
of the optic nerve head, attenuation of retinal blood vessels, and bone
spicule-like pigmentation
explanation: Bone spicule pigment on fundus examination.
- name: Attenuation of retinal blood vessels
category: Ophthalmologic
phenotype_term:
preferred_term: Attenuation of retinal blood vessels
term:
id: HP:0007843
label: Attenuation of retinal blood vessels
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Funduscopic findings at various disease stages included waxy appearance
of the optic nerve head, attenuation of retinal blood vessels, and bone
spicule-like pigmentation
explanation: Arteriolar attenuation on fundus examination.
- name: Optic disc pallor
category: Ophthalmologic
description: Waxy pallor of the optic nerve head.
phenotype_term:
preferred_term: Waxy optic disc pallor
term:
id: HP:0000543
label: Optic disc pallor
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Funduscopic findings at various disease stages included waxy appearance
of the optic nerve head, attenuation of retinal blood vessels, and bone
spicule-like pigmentation
explanation: Waxy optic nerve head appearance.
- name: Reduced visual acuity
category: Ophthalmologic
description: >-
Central acuity is lost later than rod function but can fall to 20/200 or
worse by the early thirties.
phenotype_term:
preferred_term: Reduced visual acuity
clinical_course: PROGRESSIVE
term:
id: HP:0007663
label: Reduced visual acuity
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Best-corrected visual acuity had a more prolonged time course of loss
but was 20/200 or worse in two siblings by age 30-31
explanation: Acuity loss by the fourth decade.
- name: Photoreceptor layer loss on macular OCT
category: Ophthalmologic
description: >-
By the fourth decade only a thin photoreceptor layer remains around the
fovea, and in some patients none is detectable surrounding it.
phenotype_term:
preferred_term: Photoreceptor layer loss on macular OCT
term:
id: HP:0030609
label: Photoreceptor layer loss on macular OCT
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Photoreceptor topography in a wide expanse of central retina (Figure 3E)
revealed that by the fourth decade of life, there was only a markedly
thinned photoreceptor layer remaining in and around the fovea
explanation: OCT loss of central photoreceptors.
- reference: PMID:29276052
reference_title: "Nonsyndromic Retinitis Pigmentosa in the Ashkenazi Jewish Population: Genetic and Clinical Aspects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Funduscopic findings of DHDDS patients matched those of MAK patients who
were 20 to 30 years older.
explanation: Retinal structural disease is advanced for age compared with MAK-RP.
- name: Abnormal fundus autofluorescence imaging
category: Ophthalmologic
description: >-
Abnormal macular autofluorescence pattern and widespread peripheral
decreased autofluorescence on ultra-widefield imaging, more marked than in
MAK- or FAM161A-related RP.
phenotype_term:
preferred_term: Abnormal macular and peripheral fundus autofluorescence
term:
id: HP:0030602
label: Abnormal fundus autofluorescence imaging
evidence:
- reference: PMID:35501492
reference_title: "Ultra-widefield fundus autofluorescence imaging in patients with autosomal recessive retinitis pigmentosa reveals a genotype-phenotype correlation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Specifically, DHDDS patients had a more abnormal macular FAF pattern and
more widespread decrease in peripheral autofluorescence.
explanation: Gene-specific autofluorescence pattern in 12 DHDDS patients.
- name: Cystoid macular edema
category: Ophthalmologic
frequency: OCCASIONAL
phenotype_term:
preferred_term: Cystoid macular edema
term:
id: HP:0011505
label: Cystoid macular edema
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: occasionally the presence of cystoid macular edema
explanation: Occasional cystoid macular edema on OCT.
- name: Seizure
category: Neurological
description: Reported in a single adult K42E homozygote with a multisystem CDG phenotype.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:36046393
reference_title: "Acetazolamide treatment in late onset CDG type 1 due to biallelic pathogenic DHDDS variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
An adult Ashkenazi Jewish female developed multiple symptoms of late
onset type 1 CDG including seizures, ataxia, protein losing enteropathy,
tremor, and titubation in association with elevated mono-oligo/di-oligo
transferrin ratio in blood, and classic retinitis pigmentosa.
explanation: Single case report.
- name: Ataxia
category: Neurological
description: Reported in a single adult K42E homozygote with a multisystem CDG phenotype.
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
evidence:
- reference: PMID:36046393
reference_title: "Acetazolamide treatment in late onset CDG type 1 due to biallelic pathogenic DHDDS variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
An adult Ashkenazi Jewish female developed multiple symptoms of late
onset type 1 CDG including seizures, ataxia, protein losing enteropathy,
tremor, and titubation in association with elevated mono-oligo/di-oligo
transferrin ratio in blood, and classic retinitis pigmentosa.
explanation: Single case report.
- name: Tremor
category: Neurological
description: Reported in a single adult K42E homozygote; improved on acetazolamide.
phenotype_term:
preferred_term: Tremor
term:
id: HP:0001337
label: Tremor
evidence:
- reference: PMID:36046393
reference_title: "Acetazolamide treatment in late onset CDG type 1 due to biallelic pathogenic DHDDS variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
An adult Ashkenazi Jewish female developed multiple symptoms of late
onset type 1 CDG including seizures, ataxia, protein losing enteropathy,
tremor, and titubation in association with elevated mono-oligo/di-oligo
transferrin ratio in blood, and classic retinitis pigmentosa.
explanation: Single case report.
- name: Titubation
category: Neurological
description: Reported in a single adult K42E homozygote; improved on acetazolamide.
phenotype_term:
preferred_term: Titubation
term:
id: HP:0030187
label: Titubation
evidence:
- reference: PMID:36046393
reference_title: "Acetazolamide treatment in late onset CDG type 1 due to biallelic pathogenic DHDDS variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
An adult Ashkenazi Jewish female developed multiple symptoms of late
onset type 1 CDG including seizures, ataxia, protein losing enteropathy,
tremor, and titubation in association with elevated mono-oligo/di-oligo
transferrin ratio in blood, and classic retinitis pigmentosa.
explanation: Single case report.
- name: Protein-losing enteropathy
category: Gastrointestinal
description: Reported in a single adult K42E homozygote with generalized edema.
phenotype_term:
preferred_term: Protein-losing enteropathy
term:
id: HP:0002243
label: Protein-losing enteropathy
evidence:
- reference: PMID:36046393
reference_title: "Acetazolamide treatment in late onset CDG type 1 due to biallelic pathogenic DHDDS variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
An adult Ashkenazi Jewish female developed multiple symptoms of late
onset type 1 CDG including seizures, ataxia, protein losing enteropathy,
tremor, and titubation in association with elevated mono-oligo/di-oligo
transferrin ratio in blood, and classic retinitis pigmentosa.
explanation: Single case report.
biochemical:
- name: Increased plasma and urinary dolichol-18 to dolichol-19 ratio
presence: Present in affected individuals; intermediate in carriers
context: >-
Plasma and urine, liquid chromatography-mass spectrometry. Dolichol-18
replaces dolichol-19 as the dominant species; the D18/D19 ratio separates
patients from carriers and carriers from non-carriers.
evidence:
- reference: PMID:24078709
reference_title: "Aberrant dolichol chain lengths as biomarkers for retinitis pigmentosa caused by impaired dolichol biosynthesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Receiver operating characteristic (ROC) analysis shows that plasma and
urinary D18/D19 ratios can unambiguously discriminate patients from
carriers, and carriers from normal individuals.
explanation: Diagnostic performance of the dolichol ratio.
- name: Serum transferrin glycosylation
presence: Usually normal
context: >-
Serum or plasma transferrin isoelectric focusing. Normal in all members of
the index exome family; one adult K42E homozygote with a multisystem
phenotype had an elevated mono-oligo/di-oligo transferrin ratio.
evidence:
- reference: PMID:24664694
reference_title: "Mutation K42E in dehydrodolichol diphosphate synthase (DHDDS) causes recessive retinitis pigmentosa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patterns of plasma transferrin isoelectric focusing gel were normal in
all family members, indicating no significant abnormality in protein
glycosylation.
explanation: Normal transferrin glycosylation in K42E homozygotes.
diagnosis:
- name: DHDDS molecular genetic testing
description: >-
Diagnosis is confirmed by biallelic DHDDS variants on inherited retinal
disease panel or exome sequencing. In patients of Ashkenazi Jewish
ancestry, targeted testing for K42E together with the MAK Alu insertion
explains about a third of recessive RP and can precede panel testing.
diagnosis_term:
preferred_term: Genetic Testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:25255364
reference_title: "Two specific mutations are prevalent causes of recessive retinitis pigmentosa in North American patients of Jewish ancestry."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Therefore, their screening constitutes an alternative procedure to
large-scale tests for patients belonging to this ethnic group,
especially in time-sensitive situations.
explanation: Founder-allele screening strategy for Jewish-ancestry patients.
- name: Full-field electroretinography and retinal examination
description: >-
Full-field ERG documents rod and cone dysfunction, usually nondetectable
responses by the time of referral; fundus examination shows the classic
RP triad.
diagnosis_term:
preferred_term: Retinal Examination
term:
id: NCIT:C101217
label: Retinal Examination
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ERG responses were nondetectable in most patients (Table S2).
explanation: ERG findings in genetically confirmed patients.
- name: Optical coherence tomography
description: >-
OCT shows centripetal loss of the photoreceptor layer, early relative
foveal sparing and occasional cystoid macular edema.
diagnosis_term:
preferred_term: Optical Coherence Tomography
term:
id: NCIT:C20828
label: Optical Coherence Tomography
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
OCT imaging in early disease showed preserved central retinal
photoreceptors but a decline in photoreceptor layer thickness with
distance from the fovea
explanation: OCT findings in K42E patients.
- name: Plasma or urinary dolichol profiling
description: >-
Mass-spectrometric D18/D19 dolichol ratio as a biochemical test that is
complementary to genotyping and also identifies carriers.
diagnosis_term:
preferred_term: Laboratory Procedure
term:
id: NCIT:C25294
label: Laboratory Procedure
evidence:
- reference: PMID:24078709
reference_title: "Aberrant dolichol chain lengths as biomarkers for retinitis pigmentosa caused by impaired dolichol biosynthesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dolichol profiling, complementary to genotyping, can be readily adapted
as a test in the clinic not only for the diagnosis of patients but also
for identification of carriers with DHDDS or other genetic mutations
that may impair dolichol biosynthesis.
explanation: Proposed clinical use of dolichol profiling.
treatments:
- name: Acetazolamide
description: >-
Used in a single adult K42E homozygote with a late-onset multisystem type 1
CDG phenotype, in whom it improved titubation, tremor and generalized
edema. There is no evidence that it affects the retinal degeneration, and
no disease-modifying therapy for RP59 exists.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: acetazolamide
term:
id: CHEBI:27690
label: acetazolamide
target_mechanisms:
- target: Tremor
- target: Titubation
evidence:
- reference: PMID:36046393
reference_title: "Acetazolamide treatment in late onset CDG type 1 due to biallelic pathogenic DHDDS variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
She was started on Acetazolamide and responded well to the treatment
which improved her titubation, tremor, and generalized edema.
explanation: Single-patient response.
- name: Carbonic anhydrase inhibitors for RP-associated cystoid macular edema
description: >-
Oral acetazolamide or methazolamide, or topical dorzolamide, are used for
cystoid macular edema complicating retinitis pigmentosa. The supporting
evidence is pooled across genetically unselected RP; no RP59-specific
treatment data exist. Symptomatic only; does not alter the degeneration.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: acetazolamide
term:
id: CHEBI:27690
label: acetazolamide
- preferred_term: methazolamide
term:
id: CHEBI:6822
label: Methazolamide
- preferred_term: dorzolamide
term:
id: CHEBI:4702
label: dorzolamide
target_mechanisms:
- target: Cystoid macular edema
evidence:
- reference: PMID:42493417
reference_title: "Comparative efficacy of different treatment modalities in the management of macular oedema in retinitis pigmentosa: a systematic review and network meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At 3-4 months, DEXi, acetazolamide, methazolamide and dorzolamide
demonstrated comparable CMT reduction and outperformed anti-VEGF
therapies, IVTA, STTA, intravenous UCMSC and control.
explanation: >-
Network meta-analysis of RP-associated macular edema across RP genotypes;
applies to RP59 only by extension.
animal_models:
- name: Rod-specific Dhdds knockout mouse
species: Mus musculus
genotype: Dhdds flx/flx; Rho-iCre75
publication: PMID:32526701
description: >-
Conditional ablation of Dhdds in rods. Mild dysfunction at 4 weeks is
followed by almost complete loss of rods and cones by 6 weeks despite
preserved retinal protein N-glycosylation.
genes:
- preferred_term: DHDDS
term:
id: hgnc:20603
label: DHDDS
modeled_mechanisms:
- target: Rod Photoreceptor Degeneration
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
limitations: >-
Complete rod-specific gene ablation rather than a patient hypomorphic
allele; degeneration is far faster than in patients and cones are lost
within weeks.
evidence:
- reference: PMID:32526701
reference_title: "Retinal Degeneration Caused by Rod-Specific Dhdds Ablation Occurs without Concomitant Inhibition of Protein N-Glycosylation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
rapid photoreceptor degeneration ensued, resulting in almost complete
loss of rods and cones by PN 6 weeks
explanation: Photoreceptor degeneration after rod-specific ablation.
- target: Impaired Photoreceptor Protein N-Glycosylation
relationship: FAILS_TO_RECAPITULATE
fidelity: UNKNOWN
limitations: >-
Residual dolichol pools may sustain glycosylation until degeneration,
so absence of hypoglycosylation in this model does not exclude a
transient or protein-specific defect.
evidence:
- reference: PMID:32526701
reference_title: "Retinal Degeneration Caused by Rod-Specific Dhdds Ablation Occurs without Concomitant Inhibition of Protein N-Glycosylation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Retina dolichol levels were markedly decreased by PN 4 weeks in
Dhddsflx/flx iCre+ mice, relative to controls; despite this,
N-glycosylation of retinal proteins, including opsin (the dominant
rod-specific glycoprotein), persisted in Dhddsflx/flx iCre+ mice.
explanation: Opsin glycosylation is preserved in the model.
- name: RPE-specific Dhdds knockout mouse
species: Mus musculus
genotype: Dhdds flx/flx; VMD2-Cre
publication: PMID:32245241
description: >-
Conditional ablation of Dhdds in the retinal pigment epithelium, producing
RPE atrophy, RPE transmigration and secondary photoreceptor loss with large
scotopic ERG reductions by three months.
genes:
- preferred_term: DHDDS
term:
id: hgnc:20603
label: DHDDS
modeled_mechanisms:
- target: Retinal Pigment Epithelium Dysfunction
relationship: PERTURBS
fidelity: UNKNOWN
limitations: >-
Tissue-restricted null allele; whether RPE is primarily affected by the
patient hypomorphic alleles is not established.
evidence:
- reference: PMID:32245241
reference_title: "Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These results indicate that RPE dysfunction contributes to DHDDS
mutation-mediated pathology and suggests a more complicated disease
mechanism than simply disruption of glycosylation.
explanation: RPE Dhdds loss drives retinal degeneration.
- name: Dhdds K42E knock-in mouse
species: Mus musculus
genotype: Dhdds K42E/K42E
publication: PMID:32272552
description: >-
CRISPR knock-in of the human founder allele. No overt photoreceptor
degeneration or N-glycosylation defect, but marked gliosis, shortened
dolichols in retina, liver and brain, selective ERG b-wave loss, inner
nuclear layer thinning and outer plexiform layer disruption.
genes:
- preferred_term: DHDDS
term:
id: hgnc:20603
label: DHDDS
modeled_mechanisms:
- target: Dolichol Chain-Length Shortening
relationship: RECAPITULATES
fidelity: HIGH
evidence:
- reference: PMID:37443173
reference_title: "A Dhdds K42E knock-in RP59 mouse model shows inner retina pathology and defective synaptic transmission."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Here, we report that the Dol isoprenylogue species in retina, liver,
and brain of the K42E mouse model are statistically shorter than in the
corresponding tissues of age-matched controls, as reported in blood and
urine of RP59 patients.
explanation: The human biochemical signature is reproduced.
- target: Rod Photoreceptor Degeneration
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
limitations: >-
Mouse retina lacks a macula and fovea, and outer nuclear layer thickness
is preserved to at least 12 months, whereas patients lose rod function by
their twenties.
evidence:
- reference: PMID:32272552
reference_title: "Lack of Overt Retinal Degeneration in a K42E Dhdds Knock-In Mouse Model of RP59."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Hence, retinas of DhddsK42E/K42E mice exhibited no overt signs of
degeneration, yet were markedly gliotic, but without evidence of
compromised protein N-glycosylation.
explanation: No overt degeneration in the knock-in retina.
- target: Photoreceptor-to-Bipolar Cell Synaptic Transmission Defect
relationship: RECAPITULATES
fidelity: UNKNOWN
limitations: >-
The node is defined from this model; a b-wave-selective defect has not
been demonstrated in patients, most of whom have nondetectable ERGs.
evidence:
- reference: PMID:37443173
reference_title: "A Dhdds K42E knock-in RP59 mouse model shows inner retina pathology and defective synaptic transmission."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Electroretinograms (ERGs) of mutant mice exhibited reduced b-wave
amplitudes beginning at PN 1-mo, progressively declining through PN
18-mo, without appreciable a-wave attenuation, relative to controls.
explanation: Functional readout of the synaptic defect.
- name: Dhdds T206A knock-in mice
species: Mus musculus
genotype: Dhdds T206A/T206A and T206A/K42E
publication: PMID:40574710
description: >-
Knock-in of the second patient allele, homozygous and in trans with K42E,
reproducing the K42E phenotype of b-wave loss with spared a-wave, inner
nuclear layer thinning and reduced bipolar and amacrine cell densities.
genes:
- preferred_term: DHDDS
term:
id: hgnc:20603
label: DHDDS
modeled_mechanisms:
- target: Inner Nuclear Layer Thinning with Bipolar and Amacrine Cell Loss
relationship: RECAPITULATES
fidelity: UNKNOWN
limitations: >-
Inner retinal thinning has not been specifically documented in RP59
patients.
evidence:
- reference: PMID:40574710
reference_title: "Dhdds T206A and Dhdds K42E knock-in mouse models of retinitis pigmentosa 59 are phenotypically similar."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Consistent with a reduction in inner nuclear layer thickness as seen by
using optical coherence tomography (OCT), cell loss observed by
histology, as well as bipolar and amacrine cell densities were reduced
in all Dhdds mutant phenotypes compared to those of PN 8-12 mo
age-matched controls.
explanation: >-
Reduced inner nuclear layer thickness and bipolar and amacrine cell
densities in T206A/T206A and T206A/K42E mice, the node's defining
readouts.
- name: dhdds morphant zebrafish
species: Danio rerio
genotype: dhdds morpholino knockdown
publication: PMID:24664742
description: >-
Morpholino knockdown of dhdds; larvae look normal but fail to respond to
light-off, and photoreceptor outer segments are short or absent.
genes:
- preferred_term: DHDDS
term:
id: hgnc:20603
label: DHDDS
modeled_mechanisms:
- target: Rod Photoreceptor Degeneration
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
limitations: >-
Transient knockdown in developing larvae; outer segments fail to form or
are lost, which is not equivalent to degeneration of mature
photoreceptors in young adults.
evidence:
- reference: PMID:24664742
reference_title: "Knock-down DHDDS expression induces photoreceptor degeneration in zebrafish."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These results demonstrate that suppression of DHDDS expression in
zebrafish leads to the loss of photoreceptor outer segments and visual
function.
explanation: Outer segment and visual loss after knockdown.
- name: GMR-driven CG10778 RNAi Drosophila
species: Drosophila melanogaster
genotype: GMR-Gal4 > UAS-CG10778 RNAi (DHDDS ortholog)
publication: PMID:34290587
description: >-
Eye-targeted knockdown of the fly DHDDS ortholog causes a distinctive
pattern of photoreceptor degeneration with reduced rhodopsin and
endoplasmic reticulum accumulation.
modeled_mechanisms:
- target: Rod Photoreceptor Degeneration
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
limitations: >-
Invertebrate rhabdomeric photoreceptors differ structurally from
vertebrate rods, and knockdown in the developing eye does not model a
hypomorphic allele.
evidence:
- reference: PMID:34290587
reference_title: "Knockdown of Dehydrodolichyl Diphosphate Synthase in the Drosophila Retina Leads to a Unique Pattern of Retinal Degeneration."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Western blot analysis revealed a drastic reduction in rhodopsin levels
in GMR-DHDDS-RNAi-flies and TEM sections showed an abnormal
accumulation of endoplasmic reticulum (ER).
explanation: Photoreceptor degeneration with rhodopsin loss.
discussions:
- discussion_id: rp59_nonsyndromic_gap
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Why does a partial loss of a ubiquitously required dolichol-synthesis
enzyme cause disease confined to the retina in almost all patients?
attaches_to:
- pathophysiology#DHDDS Cis-Prenyltransferase Partial Loss of Function
- pathophysiology#Systemic Protein Hypoglycosylation
rationale: >-
DHDDS is expressed in every tissue tested and dolichol chain shortening is
measurable in blood, urine, liver and brain, yet systemic involvement has
been reported only once. Candidate explanations include photoreceptor
demand for dolichol in outer-segment membrane renewal, cell-type
differences in residual activity, and genetic modifiers such as ALG6.
evidence:
- reference: PMID:21295282
reference_title: "A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: RT-PCR analysis in 21 human tissues revealed ubiquitous expression of DHDDS.
explanation: Ubiquitous expression contrasts with retina-restricted disease.
- reference: PMID:36362109
reference_title: "Vertebrate Animal Models of RP59: Current Status and Future Prospects."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Finally, to date, none of the mouse models have shed light on the reason
why RP59 is non-syndromic.
explanation: The question is explicitly open.
- discussion_id: rp59_k42e_mouse_mismatch
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Does the K42E knock-in mouse, which develops inner-retinal synaptic
dysfunction without photoreceptor loss, model the human rod-cone
degeneration, or is the photoreceptor phenotype species-specific?
attaches_to:
- pathophysiology#Rod Photoreceptor Degeneration
- pathophysiology#Photoreceptor-to-Bipolar Cell Synaptic Transmission Defect
- animal_models#Dhdds K42E knock-in mouse
rationale: >-
The patient allele in mice reproduces the dolichol shortening but not the
defining photoreceptor degeneration, while the human disease is a
rod-cone dystrophy with early macular involvement. Mice lack a macula,
and a b-wave-selective defect has not been sought in early-stage
patients, so the synaptic mechanism may be a mouse feature or an early
human feature that is masked by the time ERGs are recorded.
evidence:
- reference: PMID:32272552
reference_title: "Lack of Overt Retinal Degeneration in a K42E Dhdds Knock-In Mouse Model of RP59."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Retinas of DhddsK42E/K42E mice exhibited grossly normal histological
organization from 1 to 12 months of age.
explanation: The knock-in mouse lacks the human photoreceptor degeneration.
- reference: PMID:36362109
reference_title: "Vertebrate Animal Models of RP59: Current Status and Future Prospects."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Additionally, unlike the human or nonhuman primate retina, the mouse
retina lacks a cone-rich macula or fovea.
explanation: Anatomical basis for the species mismatch.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Retinitis Pigmentosa 59 · 2026-09-30T20:32:50Z · View source
New entry for retinitis pigmentosa 59 (MONDO:0013468), autosomal recessive DHDDS-related rod-cone dystrophy, curated from the claimed stub (stub deleted). Sources. Primary literature was gathered by PubMed search for DHDDS with retinitis pigmentosa, K42E and retina (all 33 hits screened), then cross-checked against an OpenScientist deep-research report (research/Retinitis_Pigmentosa_59-deep-research-openscientist.md). The report resolved 17/17 references (confabulation_rate 0.0, off_topic 0, 13 on topic, 4 undecided) and has no needs_review flag; quotes were not checked by the run. Its term section lists mislabelled CURIEs (for example NCIT:C233 given as acetazolamide, NCIT:C61796 as N-acetylcysteine) and the obsolete GO:0019408; none of these were used, and every CURIE in the entry was looked up in OLS or the term caches. just preflight-dr returned SKIP because it reads no RO:0004003 causal gene for MONDO:0013468; the MONDO record carries the gene only as an intersection_of axiom (RO:0004003 HGNC:20603). A manual check passed: the report cites OMIM 613861, matching MONDO, and DHDDS is its dominant gene (44 mentions). From the report's citations the entry uses PMID:42493417 (carbonic anhydrase inhibitors for RP macular edema); PMID:40003936 (DHDDS patient fibroblasts, neurodevelopmental context) was not used as out of scope, and the report's gnomAD allele-frequency figures were not used because they have no citable record. The report's claim that T206A occurs homozygously in patients was not adopted: the cited review states T206A has only been seen in trans with K42E. Content. Pathophysiology is a chain from DHDDS cis-prenyltransferase partial loss of function to dolichol chain shortening, then to four hypothesis-tagged branches: photoreceptor hypoglycosylation (ALTERNATIVE, with REFUTE evidence from normal transferrin and two mouse models), glycosylation-independent photoreceptor dolichol deficit, the knock-in mouse inner-retinal synaptic defect, and RPE contribution. Rod degeneration and secondary cone loss conform to photoreceptor_degeneration nodes; the rare systemic hypoglycosylation node (one adult K42E homozygote) conforms to congenital_disorder_of_glycosylation#Protein Hypoglycosylation. All 16 phenotypes are causally connected. Animal models cover rod- and RPE-specific knockouts, K42E and T206A knock-ins, zebrafish morphants and Drosophila RNAi, with FAILS_TO_RECAPITULATE links for the K42E mouse and rod knockout where they diverge from the human disease. The ClinGen Definitive classification for DHDDS is made against DHDDS-CDG (MONDO:1040054), not this term, so it is noted but not copied into gene_disease_validity. The dominant de novo DHDDS neurodevelopmental disorder and the fatal infantile compound-heterozygous DHDDS-CDG case are recorded as out of scope in notes. GeneReviews: only the Nonsyndromic RP Overview (PMID:20301590) exists; it is tagged, and its PubMed record carries no DHDDS-specific phenotypes. Groupings. Added a Retinitis Pigmentosa 59 member row (member_type DISEASE, DHDDS gene, dolichol-backbone biosynthesis as the proximal lesion, module photoreceptor_degeneration#Photoreceptor Gene Defect) to kb/groupings/Retinitis_Pigmentosa.yaml, and added RP59/MONDO:0013468 to that grouping's MONDO consistency note as a direct is-a child of MONDO:0019200. just check-groupings evaluates RP59 as SATISFIED on the grouping's NECESSARY criterion through both the photoreceptor_degeneration#Rod Photoreceptor Apoptosis conformance arm and the rod-cone dystrophy arm. The entry was deliberately not added to kb/groupings/Congenital_Disorders_of_Glycosylation.yaml. That grouping's NECESSARY criterion requires a defect that perturbs protein N-glycosylation. The entry's GO:0006487 annotations sit on a HYPOTHETICAL node carrying REFUTE evidence and on a single-case systemic node, so the evaluator's leaf match would be spurious. The reasoning is recorded in the entry's notes. Reference titles. Every one of the 88 evidence items carries a reference_title copied by script from the title frontmatter of its references_cache file, so no title was typed by hand. Review round 1 (PR 13291). Added quote_role BACKGROUND to both PMID:32817466 items, which restate earlier kinetics and chain-length work inside a structural paper. The PMID:24664694 catalytic-efficiency sentence states an enzyme property that the family report does not measure, so it is now quote_role BACKGROUND with evidence_source IN_VITRO. The PMID:21295282 immunohistochemistry and 21-tissue RT-PCR sentences are now IN_VITRO, since both describe ex vivo tissue work; that paper's clinical sentences stay HUMAN_CLINICAL. The T206A knock-in link to the inner nuclear layer node now quotes the PMID:40574710 sentence on reduced inner nuclear layer thickness and bipolar and amacrine cell densities instead of the general common-mechanism conclusion. A notes sentence records that the NAC Attack phase III trial (PMID:39864434) is for retinitis pigmentosa in general and is not curated as an RP59 treatment. Validation. just validate, validate-terms, count-verified-snippets (88/88), check-entity-refs, check-causal-targets, check-duplicate-keys, check-coarse-phenotypes, check-folded-hyphens, check-environmental-evidence, check-enum-values, check-qualifier-terms, list-gene-term-mismatches (no findings) and just validate-disorders all pass. check-snippet-length, check-title-snippets and check-snippet-grading pass in their default --against-ref origin/main mode.
Disease: Retinitis Pigmentosa 59 | OMIM: #613861 | MONDO: MONDO:0013468 | Gene: DHDDS (OMIM *608172) | Category: Mendelian (autosomal recessive)
Retinitis Pigmentosa 59 (RP59) is a rare, non-syndromic, autosomal recessive rod–cone dystrophy caused by biallelic missense variants in DHDDS (dehydrodolichyl diphosphate synthase), the catalytic subunit of the endoplasmic-reticulum cis-prenyltransferase (cis-PT) complex that synthesizes dolichol — the obligate lipid carrier for protein N-glycosylation. The disease is defined biochemically by a hypomorphic enzymatic defect: the recurrent K42E (c.124A>G, p.Lys42Glu) allele lowers catalytic efficiency and shortens dolichol chains (yielding a diagnostic elevation of the dolichol-18/dolichol-19 ratio) without producing a gross serum hypoglycosylation defect. K42E is an Ashkenazi Jewish (AJ) founder mutation, accounting for ~33% of genetically solved AJ retinitis pigmentosa families and carried by roughly 1 in 91 people of AJ ancestry (gnomAD v4 ASJ allele frequency 0.55%).
Clinically, RP59 presents as a classic rod-cone dystrophy — night blindness, progressive peripheral-then-central visual-field loss, bone-spicule retinal pigmentation, and an attenuated or extinguished electroretinogram (ERG) — but with unusually prominent macular and retinal-pigment-epithelium (RPE) involvement that gives a distinctive fundus autofluorescence signature. This distinguishes DHDDS-RP from other genetic RP subtypes and hints at a mechanism extending beyond pure photoreceptor loss. Multiple knock-in and conditional mouse models (K42E, T206A, RPE-specific Dhdds ablation) localize early pathology to the inner retina — thinning of the inner nuclear layer, reduced bipolar/amacrine cell densities, and defective photoreceptor-to-bipolar synaptic transmission — as well as to the RPE, rather than to primary outer-segment degeneration.
There is currently no gene-specific cure. Management is supportive: carbonic-anhydrase inhibitors for cystoid macular edema, cataract surgery, low-vision rehabilitation, and genetic counseling with founder-variant carrier screening in Ashkenazi Jews. Antioxidant (N-acetylcysteine) and broad gene-based therapies for RP are in development. Importantly, DHDDS is an allelic locus for a separate, dominant, de novo neurodevelopmental/neurodegenerative disorder (DEDSM) — developmental delay, epilepsy, myoclonus, and movement disorder — which is mechanistically and genetically distinct from recessive RP59.
Overview. RP59 is a specific, rare, autosomal recessive, non-syndromic subtype of retinitis pigmentosa. Retinitis pigmentosa as a whole is a leading cause of inherited visual disability with a worldwide prevalence of approximately 1:4000 (PMID: 29597005; "RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000."). RP59 is defined by biallelic pathogenic variants in DHDDS.
Key identifiers.
| Resource | Identifier |
|---|---|
| OMIM (disease) | #613861 (Retinitis pigmentosa 59) |
| OMIM (gene) | *608172 (DHDDS) |
| MONDO | MONDO:0013468 |
| HGNC | HGNC:20603 (DHDDS) |
| UniProt | Q86SQ9 (DHDDS protein) |
| Gene locus | Chromosome 1p36.11 |
| dbSNP (K42E) | rs147394623 |
Synonyms / alternative names. RP59; DHDDS-related retinitis pigmentosa; DHDDS-associated inherited retinal degeneration (IRD). The broader DHDDS disease spectrum also includes DHDDS-congenital disorder of glycosylation (DHDDS-CDG) and DEDSM (developmental delay and seizures with or without movement abnormalities).
Source of information. The knowledge here is derived from aggregated disease-level resources (OMIM, Orphanet, gnomAD) and primary literature (case series, family-based whole-exome studies, biochemical and animal-model work), not from individual EHR records.
Disease causal factors. RP59 is a monogenic Mendelian disorder caused by biallelic (homozygous or compound heterozygous) pathogenic missense variants in DHDDS. Whole-exome sequencing of an Ashkenazi Jewish family with 3 of 4 affected siblings identified a homozygous c.124A>G (p.Lys42Glu, K42E) variant as causal (PMID: 24664694; "A single-nucleotide mutation in the gene that encodes DHDDS has been identified by whole exome sequencing as the cause of the non-syndromic recessive retinitis pigmentosa (RP) in a family of Ashkenazi Jewish origin..."). Reported RP59-causing genotypes include K42E/K42E, T206A/K42E, and R98W/K42E (PMID: 40574710; "three variant alleles (K42E/K42E, T206A/K42E and R98W/K42E) have been reported to cause retinitis pigmentosa 59 (RP59)").
Genetic risk factors. The single dominant genetic risk factor is inheritance of two pathogenic DHDDS alleles. The K42E founder allele dramatically elevates carrier risk in individuals of Ashkenazi Jewish ancestry (see Sections 4 and 9). Modifier genes in the glycosylation pathway (notably ALG6) influence expressivity (Section 4).
Environmental risk factors. No established environmental risk factors initiate RP59; the disease is fully genetically determined. General retinal-health factors (e.g., light exposure, oxidative stress) may modulate progression but are not documented as specific RP59 risk factors.
Protective factors. No validated genetic or environmental protective alleles specific to RP59 are documented. Modifier alleles can shift severity in either direction (e.g., ALG6 F304S was associated with less peripheral rod disease even while worsening macular cone disease; PMID: 38256083).
Gene–environment interactions. No specific gene-environment interaction has been established for RP59. The dominant modulatory interactions are gene–gene (glycosylation-pathway modifiers).
RP59 manifests as a progressive rod-cone dystrophy with added macular/RPE features. Key phenotypes, with suggested HPO terms:
| Phenotype | Type | HPO term | Onset / progression | Frequency |
|---|---|---|---|---|
| Night blindness (nyctalopia) | Symptom | HP:0000662 | Early, progressive | Characteristic/typical |
| Rod-cone dystrophy | Clinical sign | HP:0000510 | Early-onset, progressive | Defining feature |
| Constriction of visual field | Clinical sign | HP:0001133 | Peripheral→central, progressive | Typical |
| Bone-spicule retinal pigmentation | Physical manifestation | HP:0007737 | Progressive | Typical |
| Abnormal/attenuated or absent ERG | Lab/functional | HP:0000512 | Early, progressive | Typical/severe |
| Reduced visual acuity | Symptom/sign | HP:0007663 | Progressive, worse & earlier than MAK-RP | Common |
| Macular degeneration / maculopathy | Clinical sign | HP:0000608 | Prominent in DHDDS-RP | Characteristic |
| Retinal pigment epithelial atrophy | Clinical sign | HP:0007894 | Progressive | Common |
Characteristics. DHDDS-RP59 patients exhibit classic RP symptoms (night blindness, progressive peripheral then central visual field loss, bone-spicule pigmentation, attenuated ERG) plus macular changes suggestive of RPE involvement (PMID: 32245241; "Patients with certain defects in the dehydrodolichyl diphosphate synthase (DHDDS) gene (RP59; OMIM #613861) exhibit classic symptoms of retinitis pigmentosa, as well as macular changes, suggestive of retinal pigment epithelium (RPE) involvement."). On ultra-widefield fundus autofluorescence (FAF), DHDDS patients (n=12) had a significantly more abnormal macular FAF pattern and more widespread decreased peripheral autofluorescence than MAK or FAM161A RP patients (macular abnormality p=0.001) (PMID: 35501492; "DHDDS patients had a more abnormal macular FAF pattern and more widespread decrease in peripheral autofluorescence."). DHDDS patients tend to have worse visual acuity and visual fields at younger ages than MAK patients (PMID: 29276052), indicating relatively severe, earlier expressivity.
Severity / progression. Severity is moderate-to-severe and progressive, with variable expressivity influenced by modifier genes. Onset is early (see Section 8).
Quality-of-life impact. Progressive constriction of the visual field and central vision loss lead to loss of independent mobility, driving cessation, reading difficulty, and eventual legal blindness — substantial impacts on daily functioning. Disease-specific QoL instrument data for RP59 specifically were not identified; general RP QoL burden applies.
Causal gene. DHDDS (dehydrodolichyl diphosphate synthase), chromosome 1p36.11, OMIM *608172, HGNC:20603, UniProt Q86SQ9.
Pathogenic variants.
| Variant | HGVS (NM_024887.4) | Protein | Type | Role |
|---|---|---|---|---|
| K42E | c.124A>G | p.Lys42Glu | Missense | Founder hypomorph; most common RP59 allele |
| T206A | c.616A>G | p.Thr206Ala | Missense | RP59 in trans with K42E or homozygous |
| R98W | — | p.Arg98Trp | Missense | RP59 in trans with K42E |
The K42E variant changes the highly conserved residue Lys42 to Glu, resulting in lower catalytic efficiency (PMID: 24664694) — i.e., a hypomorphic, partial loss-of-function allele rather than a null. Biallelic null/severe-hypomorphic combinations (e.g., nonsense + splice) instead cause fatal infantile DHDDS-CDG, indicating an allelic dosage/severity spectrum.
Variant classification (ACMG/AMP). K42E is classified pathogenic for RP59 given segregation, functional enzyme data, and biochemical biomarker evidence. T206A and R98W are pathogenic/likely-pathogenic in the recessive RP context.
Allele frequency (gnomAD v4; computational/database evidence — Finding F012). Direct query of gnomAD v4 for variant 1-26438228-A-G (rs147394623) returns:
| Population | Allele frequency | Allele count |
|---|---|---|
| Global (exomes) | 1.29×10⁻⁴ | 188 / 1,461,728 |
| Ashkenazi Jewish (ASJ) | 0.555% | 145 / 26,132 |
| Non-Finnish European | 2.2×10⁻⁵ | 24 / 1,111,908 |
| African / East Asian / South Asian / Finnish / Mid-Eastern | ~absent | — |
This is a ~257-fold ASJ-vs-NFE enrichment. Predicted ASJ carrier frequency ≈ 2pq ≈ 1.1% (~1 in 91); predicted ASJ homozygote (affected) frequency q² ≈ 1 in ~32,000 before accounting for compound heterozygosity with T206A/R98W.
Functional consequence. Partial loss of function (reduced catalytic efficiency of cis-PT), not gain-of-function or dominant-negative, in the recessive RP context.
Modifier genes. In 11 K42E-IRD patients, an ALG6 modifier variant (F304S) correlated with greater macular cone disease severity but less peripheral rod disease severity, showing that glycosylation-pathway modifier genes influence RP59 expressivity (PMID: 38256083). Additional candidate modifiers tested include ALG8, DDOST, MPDU1, TNKS.
Epigenetic information / chromosomal abnormalities. No disease-specific DNA-methylation, histone, or large-scale chromosomal abnormality is documented for RP59; it is a point-mutation monogenic disorder.
No environmental toxins, radiation, pollution, occupational exposures, lifestyle factors, or infectious agents are established as causes or triggers of RP59. The disease is entirely genetically determined by biallelic DHDDS variants. (This section is not applicable beyond general retinal-health considerations.)
Molecular pathways / biochemistry. DHDDS is the catalytic subunit of the human cis-prenyltransferase (with NgBR/NUS1), synthesizing dehydrodolichyl diphosphate, the precursor of dolichol, the obligate lipid carrier for N-glycosylation (PMID: 33077723; "The human cis-prenyltransferase (hcis-PT) is an enzymatic complex essential for protein N-glycosylation. Synthesizing the precursor of the glycosyl carrier dolichol-phosphate, mutations in hcis-PT cause severe human diseases."). The enzyme operates in the isoprenoid/dolichol arm of the mevalonate pathway. GO terms: di-trans,poly-cis-decaprenylcistransferase activity (GO:0045547), dolichol biosynthetic process (GO:0019408), ER membrane (GO:0005789).
Protein dysfunction / structure. The human cis-PT is a heterotetramer of two catalytic DHDDS subunits and two inactive Nogo-B receptor (NgBR, gene NUS1) subunits, assembling via DHDDS C-termini as a dimer-of-heterodimers; the NgBR distal C-terminus crosses the interface to help form the DHDDS active site (2.3 Å crystal structure; PMID: 33077723; "the 2.3 Å crystal structure reveals that the tetramer assembles via the DHDDS C-termini as a dimer-of-heterodimers"). Disease mutations cluster around the active site, and molecular-dynamics simulations propose a mechanism for hcis-PT dysfunction in RP (PMID: 33077723; "we explored the functional consequences of disease mutations clustered around the active-site... we propose a mechanism for hcis-PT dysfunction in retinitis pigmentosa"). K42 is a highly conserved residue; K42E is a hypomorphic partial loss-of-function change.
Cellular processes / tissue damage. Mouse models show elevated expression of synaptogenesis/synaptic genes, progressive reduction of inner nuclear layer (INL) and total retinal thickness from ~postnatal 2 months, and INL/outer plexiform layer cell loss — without profound photoreceptor outer-segment degeneration or N-glycosylation defect (PMID: 37443173; "Quantitative retinal cell layer thickness measurements demonstrated a significant reduction in the inner nuclear layer (INL) and total retinal thickness (TRT) beginning at postnatal (PN) ∼2 months"). T206A/T206A, T206A/K42E and K42E/K42E mice show reduced INL thickness, reduced ERG b-waves with relatively spared a-waves, attenuated c- and d-waves, and reduced bipolar/amacrine densities. The authors propose that RP59 dysfunction involves defective photoreceptor-to-bipolar synaptic transmission with concomitant bipolar/amacrine cell degeneration (PMID: 40574710; "We propose that the physiological basis of retinal dysfunction in RP59 involves defective photoreceptor to bipolar cell synaptic transmission with concomitant bipolar/amacrine cell degeneration.").
RPE contribution. Selective Dhdds ablation in mouse RPE causes RPE atrophy, hyper-reflectivity, transmigration into the photoreceptor layer, and scotopic a-/b-wave reductions of 83%/77% at 3 months (PMID: 32245241), directly demonstrating an RPE-autonomous component consistent with the macular/RPE phenotype seen in patients.
Cell types (CL) and biological processes (GO). Cell types: photoreceptor (CL:0000210), rod (CL:0000604), cone (CL:0000573), retinal bipolar neuron (CL:0000748), amacrine cell (CL:0000561), retinal pigment epithelial cell (CL:0002586). Biological processes: dolichol biosynthetic process (GO:0019408), protein N-linked glycosylation (GO:0006487), synaptic transmission / photoreceptor cell maintenance.
Immune / metabolic / epigenetic. No autoimmune or infectious mechanism. The core metabolic defect is in isoprenoid/dolichol lipid metabolism. No RP59-specific epigenetic mechanism is documented.
Diagnosis rests on three complementary pillars (Finding F011):
Important negative test: Standard serum transferrin isoelectric focusing is typically normal in RP59 — "Patterns of plasma transferrin isoelectric focusing gel were normal in all family members, indicating no significant abnormality in protein glycosylation" (PMID: 24664694) — so routine CDG screening will miss RP59; dolichol profiling and/or genetics are required.
Differential diagnosis: other genetic RP subtypes (MAK, FAM161A, USH2A, RPGR), Leber congenital amaurosis, and acquired outer retinopathies (e.g., AZOOR) — distinguished by genotype and the distinctive DHDDS FAF/macular pattern.
Screening: Ashkenazi Jewish carrier screening for K42E (and cascade family testing) is the key preventive-diagnostic measure.
CHEBI terms: dolichol (CHEBI:16091), dolichyl phosphate (CHEBI:57683).
There is no approved gene-specific therapy for DHDDS-RP59 (Finding F009). Management is supportive and symptomatic.
| Intervention | Evidence / role | NCIT (suggested) |
|---|---|---|
| Carbonic-anhydrase inhibitors (oral acetazolamide, methazolamide; topical dorzolamide) | First-line for RP-associated cystoid macular edema. Network meta-analysis (12 studies) found these reduced central macular thickness and improved BCVA at 3–4 months, outperforming anti-VEGF/steroids (PMID: 42493417; "At 3-4 months, DEXi, acetazolamide, methazolamide and dorzolamide demonstrated comparable CMT reduction and outperformed anti-VEGF therapies") | Acetazolamide (NCIT:C233); Dorzolamide |
| N-acetylcysteine (NAC) | Antioxidant; Phase III "NAC Attack" trial ongoing for RP, targeting oxidative-stress-driven photoreceptor loss (PMID: 39864434; "The ongoing multicentre Phase III trial 'NAC Attack' aims to evaluate the long-term efficacy and safety of NAC in RP.") | N-Acetylcysteine (NCIT:C61796) |
| Low-vision rehabilitation, cataract surgery | Standard supportive care | Low Vision Aid |
| Gene / cell-based therapy | Investigational for RP broadly; none DHDDS-specific yet | Gene Therapy (NCIT:C15262) |
| Vitamin A palmitate | Debated in RP generally; contraindicated in some genotypes — use with caution | — |
Of note, acetazolamide improved systemic symptoms in a K42E DHDDS-CDG patient (PMID: 36046393). Personalized approach: genotype-guided counseling and modifier-aware prognostication (ALG6) are emerging.
RP59 has a rich set of engineered models (reviewed in Vertebrate Animal Models of RP59, PMID: 36362109).
| Model | Type | Key phenotype | Reference |
|---|---|---|---|
| Dhdds K42E knock-in mouse | Mammalian, knock-in | Shortened retina/liver/brain dolichols; INL & total retinal thinning from ~PN 2 mo; INL/OPL cell loss; no profound outer-segment degeneration or N-glycosylation defect; defective synaptic transmission | PMID: 37443173 |
| Dhdds T206A & K42E knock-in mice (T206A/T206A, T206A/K42E, K42E/K42E) | Mammalian, knock-in | Reduced INL thickness; reduced ERG b-waves with relatively spared a-waves; attenuated c-/d-waves; reduced bipolar/amacrine densities; phenotypically similar across genotypes | PMID: 40574710 |
| RPE-specific Dhdds ablation mouse | Mammalian, conditional KO | RPE atrophy, hyper-reflectivity, transmigration into photoreceptor layer; scotopic a-/b-wave reductions 83%/77% at 3 mo | PMID: 32245241 |
| Patient-derived cells | In vitro | Niemann-Pick C-like endolysosomal dysfunction; correctable by miglustat (in DHDDS-CDG context) | PMID: 40003936 |
Phenotype recapitulation: The knock-in models reproduce the inner-retinal and RPE features but, notably, do not show the profound photoreceptor degeneration classically expected of RP — a key insight redirecting the mechanistic focus to bipolar/amacrine synaptic pathology. Limitations: species differences in dolichol chain length and retinal architecture; incomplete modeling of human macular involvement (mice lack a macula).
Biallelic DHDDS hypomorph (K42E)
│ (reduced catalytic efficiency — demonstrated)
▼
cis-PT (DHDDS2·NgBR2 heterotetramer) makes less
dehydrodolichyl-PP → less / shorter dolichol
│ (elevated D18/D19 ratio — biomarker)
├──────────────► N-glycosylation LARGELY PRESERVED
│ (normal transferrin IEF; no gross CDG)
│
└──────────────► RETINAL / RPE DYSFUNCTION
├─ Inner retina: defective photoreceptor→bipolar
│ synaptic transmission; INL thinning;
│ bipolar/amacrine loss (mouse-demonstrated)
└─ RPE: atrophy, transmigration (mouse-demonstrated)
│
▼
Progressive rod-cone dystrophy + macular/RPE disease
→ nyctalopia, field constriction, central vision loss,
abnormal ERG/FAF (human clinical)
The central, somewhat counterintuitive insight of RP59 biology is a tissue-specific vulnerability paradox: DHDDS is essential for N-glycosylation in all cells, yet the recessive hypomorphic K42E allele produces an eye-restricted phenotype without gross systemic hypoglycosylation. The retina — and specifically the inner-retinal synaptic circuitry and RPE — appears exquisitely sensitive to the partial reduction in dolichol supply. This contrasts with the allelic dominant DEDSM disorder (de novo DHDDS variants such as R211Q, R37H) that causes a neurodevelopmental/neurodegenerative syndrome with epilepsy, myoclonus, and movement disorder (PMID: 34382076; "Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia."), and with severe biallelic null combinations that cause fatal infantile CDG. RP59 thus sits at the mild end of a DHDDS allelic dosage spectrum.
| PMID | Contribution | Supports |
|---|---|---|
| 24664694 | WES identifies K42E as cause of recessive RP; reduced catalytic efficiency; normal transferrin IEF | F001, F003, F007, F011 |
| 40574710 | RP59-causing genotypes; knock-in mice; inner-retinal synaptic mechanism | F001, F004 |
| 24078709 | Dolichol chain shortening (D18/D19) as biomarker & carrier test | F003, F011 |
| 33077723 | 2.3 Å cis-PT heterotetramer structure; mutations at active site | F003, F007 |
| 29276052 | K42E = 33% of solved AJ RP; worse phenotype than MAK | F002, F006, F010 |
| 32245241 | Macular/RPE involvement; RPE-ablation model (83%/77% ERG loss) | F006 |
| 35501492 | Distinctive DHDDS FAF/macular signature | F006, F011 |
| 37443173 | K42E knock-in: INL thinning, synaptic defect, no CDG | F003, F004 |
| 38256083 | ALG6 F304S modifier of retinal severity | F008 |
| 34382076 | De novo dominant DHDDS neurodevelopmental disorder (DEDSM) | F005, F008 |
| 40003936 | DHDDS-NgBR dolichol role; endolysosomal dysfunction; miglustat | F005 |
| 36046393 | Late-onset CDG from homozygous K42E; acetazolamide benefit | F008, F009 |
| 42493417 | Carbonic-anhydrase inhibitors first-line for RP macular edema | F009 |
| 39864434 | NAC Phase III "NAC Attack" antioxidant trial for RP | F009 |
| 29597005 | RP prevalence 1:4000; natural history | F010 |
| 36362109 | Review of RP59 vertebrate animal models | Section 15 |
| gnomAD v4 (computational) | K42E ASJ AF 0.555%; ~1 in 91 carriers; 257-fold enrichment | F012 |
Checked with linkml-reference-validator 0.3.0rc3.
| Outcome | Count |
|---|---|
| References checked | 17 |
| Resolved | 17 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 17 |
| On topic | 13 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 28 |
| Resolved | 26 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 1 |
| Terms whose name was checked | 15 |
| Terms named correctly | 1 |
| Terms named as a different term | 12 |
| Terms whose name is worth a second look | 2 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0013468 (2 mentions) - the report calls it "MONDO"; MONDO calls it retinitis pigmentosa 59HP:0000662 (1 mention) - the report calls it "Symptom"; HP calls it NyctalopiaHP:0000510 (1 mention) - the report calls it "Clinical sign"; HP calls it Rod-cone dystrophyHP:0001133 (1 mention) - the report calls it "Clinical sign"; HP calls it Constriction of peripheral visual fieldHP:0007737 (1 mention) - the report calls it "Physical manifestation"; HP calls it Spicular pigmentation of the retinaHP:0000512 (1 mention) - the report calls it "Lab/functional"; HP calls it Abnormal electroretinogramHP:0007663 (1 mention) - the report calls it "Symptom/sign"; HP calls it Reduced visual acuityHP:0000608 (1 mention) - the report calls it "Clinical sign"; HP calls it Macular degenerationHP:0007894 (1 mention) - the report calls it "Clinical sign"; HP calls it Fundus hypopigmentationUBERON:0000966 (2 mentions) - the report calls it "retina", "Organ level: Eye — specifically the retina"; UBERON calls it retinaNCIT:C233 (1 mention) - the report calls it "Acetazolamide"; NCIT calls it AminoglutethimideNCIT:C61796 (1 mention) - the report calls it "N-Acetylcysteine"; NCIT calls it IvermectinThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0019408 (obsolete dolichol biosynthetic process) (2 mentions) - replaced by GO:0043048The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
GO:0005789 (2 mentions) - the report calls it "Subcellular level: Endoplasmic reticulum membrane"; GO calls it endoplasmic reticulum membraneNCIT:C15262 (1 mention) - the report calls it "Gene Therapy"; NCIT calls it ImmunotherapyThe report gives these identifiers more than one name of its own:
UBERON:0000966 - called "retina", "Organ level: Eye — specifically the retina"