Osteootohepatoenteric syndrome is a recessive disorder of a myosin co-chaperone. UNC45A belongs to the UCS family: a C-terminal UCS domain grips the myosin motor domain, an N-terminal tetratricopeptide-repeat domain binds Hsp90, and together they fold myosins that would otherwise aggregate. Losing it produces the four-organ combination the name records - bone fragility, sensorineural hearing loss, cholestatic liver disease and congenital diarrhoea. What makes the entry worth curating as a mechanism rather than a phenotype list is that the enteropathy has a named client protein. Mass spectrometry identified myosin VB as a UNC45A client, and myosin VB is misfolded in UNC45A-null enterocyte-like cells. Myosin VB is the motor whose loss causes microvillus inclusion disease, so the chain from chaperone to enteropathy runs through a second, already-characterized disease gene: UNC45A loss reduces functional myosin VB, recycling endosomes are mispositioned, apical cargo is not delivered, and the brush border is internalized as microvillus inclusions. Patient organoids and patient duodenal biopsies show the microvillus-inclusion picture, and so do zebrafish enterocytes. The liver has a mechanism too, and a more recent one: a patient liver biopsy shows reduced UNC45A together with reduced and mislocalized bile salt export pump in hepatocytes, which is a canalicular export failure and explains the low-GGT cholestasis. Hearing and bone are curated honestly as phenotypes with no mechanism at all. The chaperone is ubiquitous and nonmuscle myosin II is also its client, so a cochlear or skeletal mechanism is easy to hypothesize and none has been demonstrated; this entry does not invent the chain. Not every allele is a simple loss of function, and the entry models that. The recurrent p.Leu237Pro variant retains chaperone activity and folds nonmuscle myosin II correctly, but forms atypically stable oligomers that will not let go of the folded myosin - so it fails by holding on rather than by not working. It is curated as a separate node with functional_impact_category NEOMORPHIC, because collapsing it into the loss-of-function node would make the entry state something the 2025 analysis explicitly contradicts. One pathophysiology node declares conforms_to against kb/modules/enterocyte_polarity_trafficking_failure, entering through the trafficking arm (`#Loss of Apical Delivery Machinery`) and not the adhesion arm, as that module's description requires. This disease is a step upstream of the module's canonical MYO5B lesion rather than a variant of it. Only about a dozen patients have been reported, so every claim here is small-n and much of the mechanism is cell-line and zebrafish work rather than human.
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name: Osteootohepatoenteric Syndrome
creation_date: "2026-09-11T12:50:00Z"
category: Mendelian
synonyms:
- O2HE syndrome
- osteo-oto-hepato-enteric syndrome
- UNC45A deficiency
- cholestasis, diarrhea, impaired hearing and bone fragility syndrome
description: >-
Osteootohepatoenteric syndrome is a recessive disorder of a myosin
co-chaperone. UNC45A belongs to the UCS family: a C-terminal UCS domain grips
the myosin motor domain, an N-terminal tetratricopeptide-repeat domain binds
Hsp90, and together they fold myosins that would otherwise aggregate. Losing
it produces the four-organ combination the name records - bone fragility,
sensorineural hearing loss, cholestatic liver disease and congenital diarrhoea.
What makes the entry worth curating as a mechanism rather than a phenotype
list is that the enteropathy has a named client protein. Mass spectrometry
identified myosin VB as a UNC45A client, and myosin VB is misfolded in
UNC45A-null enterocyte-like cells. Myosin VB is the motor whose loss causes
microvillus inclusion disease, so the chain from chaperone to enteropathy runs
through a second, already-characterized disease gene: UNC45A loss reduces
functional myosin VB, recycling endosomes are mispositioned, apical cargo is
not delivered, and the brush border is internalized as microvillus inclusions.
Patient organoids and patient duodenal biopsies show the microvillus-inclusion
picture, and so do zebrafish enterocytes.
The liver has a mechanism too, and a more recent one: a patient liver biopsy
shows reduced UNC45A together with reduced and mislocalized bile salt export
pump in hepatocytes, which is a canalicular export failure and explains the
low-GGT cholestasis. Hearing and bone are curated honestly as phenotypes with
no mechanism at all. The chaperone is ubiquitous and nonmuscle myosin II is
also its client, so a cochlear or skeletal mechanism is easy to hypothesize and
none has been demonstrated; this entry does not invent the chain.
Not every allele is a simple loss of function, and the entry models that. The
recurrent p.Leu237Pro variant retains chaperone activity and folds nonmuscle
myosin II correctly, but forms atypically stable oligomers that will not let go
of the folded myosin - so it fails by holding on rather than by not working.
It is curated as a separate node with functional_impact_category NEOMORPHIC,
because collapsing it into the loss-of-function node would make the entry state
something the 2025 analysis explicitly contradicts.
One pathophysiology node declares conforms_to against
kb/modules/enterocyte_polarity_trafficking_failure, entering through the
trafficking arm (`#Loss of Apical Delivery Machinery`) and not the adhesion
arm, as that module's description requires. This disease is a step upstream of
the module's canonical MYO5B lesion rather than a variant of it.
Only about a dozen patients have been reported, so every claim here is small-n
and much of the mechanism is cell-line and zebrafish work rather than human.
disease_term:
preferred_term: osteootohepatoenteric syndrome
term:
id: MONDO:0859164
label: osteootohepatoenteric syndrome
parents:
- Congenital diarrheal disorder
- Inborn error of metabolism
inheritance:
- name: Autosomal Recessive
description: >-
Biallelic UNC45A variants, homozygous or compound heterozygous, confirmed by
trio exome sequencing with parental segregation in the original families.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:29429573
reference_title: "Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder."
explanation: "Trio sequencing with biallelic variants in affected individuals, which is the basis for the recessive assignment."
pathophysiology:
- name: Biallelic UNC45A Loss of Function
biological_scale: MOLECULAR
description: >-
Two mechanistic classes of allele converge on the same endpoint. Nonsense and
frameshift alleles abolish the protein outright. Missense alleles are subtler
and more informative: several are expressed at normal levels in transfected
cells yet still fail to rescue, and for the p.Val423Asp allele the defect was
shown to be protein instability rather than loss of a specific function.
Thr230 and Leu237 both map to the third armadillo repeat of the central
domain, the segment that connects the Hsp90-binding and myosin-binding ends.
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
evidence:
- reference: PMID:29429573
reference_title: "Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function."
explanation: "States the functional-impact category assigned to this node, from the paper that established the gene-disease relationship."
- reference: PMID:35421597
reference_title: "A Functional Relationship Between UNC45A and MYO5B Connects Two Rare Diseases With Shared Enteropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Protein instability rather than functional impairment underlies the pathogenicity of the O2HE syndrome-associated UNC45A-p.V423D mutation."
explanation: >-
Distinguishes the mechanism of one missense allele. Worth recording because
it means the allele is not a separation-of-function reagent, and it is the
only allele whose mechanism has been resolved this precisely.
downstream:
- target: Loss of UNC45A Myosin Co-Chaperone Function
causal_link_type: DIRECT
evidence:
- reference: PMID:35575086
reference_title: "UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In keeping with impaired myosin VB function, UNC45AKO Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles."
explanation: >-
Rescue by wild-type and failure of rescue by the patient alleles is what
licenses treating the variants as acting through loss of the chaperone
function rather than through some neomorphic effect.
- name: Loss of UNC45A Myosin Co-Chaperone Function
biological_scale: MOLECULAR
description: >-
UNC45A is a UCS-family myosin co-chaperone with a three-domain architecture:
the C-terminal UCS domain binds the myosin motor domain, the N-terminal
tetratricopeptide-repeat domain binds Hsp90, and a central domain connects
them. Vertebrates carry two non-redundant isoforms; UNC45B is confined to
striated muscle and causes myopathy, while UNC45A is ubiquitous. That
division is why this disease is not a myopathy.
molecular_functions:
- preferred_term: myosin co-chaperone activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0044183
label: protein folding chaperone
evidence:
- reference: PMID:35575086
reference_title: "UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking."
supports: SUPPORT
evidence_source: OTHER
snippet: "All UNC45 proteins share the same 3-domain organization, with a C-terminal UCS domain, which binds the motor domain of myosin, a less-conserved central domain of unknown function and an N-terminal tetratricopeptide repeat (TPR) domain that binds to Hsp90."
explanation: >-
Describes the molecular architecture this node loses. Background prose in
the paper's introduction rather than its own result, hence OTHER.
- reference: PMID:35421597
reference_title: "A Functional Relationship Between UNC45A and MYO5B Connects Two Rare Diseases With Shared Enteropathy."
supports: SUPPORT
evidence_source: OTHER
snippet: "UNC45A is a myosin (co-)chaperone, and mutations in the UNC45A gene were recently identified in osteo-oto-hepato-enteric (O2HE) syndrome patients presenting with congenital diarrhea and intrahepatic cholestasis."
explanation: >-
States the protein's function and ties it to this disease. The paper is
an in vitro study, but this particular sentence is its opening background
statement rather than one of its results, so it is graded OTHER for the
same reason as the architecture quote above it. It had been graded
IN_VITRO from the paper's overall design, which is the wrong unit: the
grading belongs to the passage.
downstream:
- target: Bile Salt Export Pump Mislocalization
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Which myosin client carries the hepatic defect is not established; the
observation is that the chaperone and the transporter are both reduced in
the same biopsy.
evidence:
- reference: PMID:41861679
reference_title: "Odevixibat treatment for recurrent cholestasis in a patient with biallelic UNC45A variants causing osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immunofluorescence microscopy of the liver specimen archived at age 10 showed reduced expression of the UNC45A protein and reduced expression and aberrant localization of the bile salt export pump (BSEP) in hepatocytes"
explanation: >-
Co-observation of reduced chaperone and mislocalized transporter in one
specimen. The intervening client is unknown, hence the indirect link type.
- target: Myosin VB Misfolding and Depletion
causal_link_type: DIRECT
evidence:
- reference: PMID:35575086
reference_title: "UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45AKO Caco-2 cells."
explanation: >-
Client identification plus the misfolding phenotype in the knockout, which
is the chaperone-to-client step this edge asserts.
- name: Myosin VB Misfolding and Depletion
biological_scale: MOLECULAR
description: >-
Myosin VB is the recycling-endosome motor. Without its co-chaperone it
misfolds and its protein level falls, in hepatic as well as intestinal cells.
This is the node that connects osteootohepatoenteric syndrome to microvillus
inclusion disease, whose cause is loss of myosin VB itself.
molecular_functions:
- preferred_term: myosin VB motor function
modifier: DECREASED
term:
id: GO:0000146
label: microfilament motor activity
evidence:
- reference: PMID:35421597
reference_title: "A Functional Relationship Between UNC45A and MYO5B Connects Two Rare Diseases With Shared Enteropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "UNC45A depletion in intestinal and hepatic cells reduced myosin Vb protein expression, and in intestinal epithelial cells, it affected 2 myosin Vb-dependent processes that underlie MVID pathogenesis: rat sarcoma-associated binding protein (RAB)11A-positve recycling endosome positioning and microvilli development."
explanation: >-
Both the depletion itself and the two downstream processes it disturbs. Note
the depletion is also shown in hepatic cells, which is the only molecular
thread to the liver phenotype.
downstream:
- target: Apical Trafficking and Recycling Endosome Failure
causal_link_type: DIRECT
evidence:
- reference: PMID:35421597
reference_title: "A Functional Relationship Between UNC45A and MYO5B Connects Two Rare Diseases With Shared Enteropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "A functional relationship exists between UNC45A and myosin Vb, thereby connecting 2 rare congenital diseases with overlapping enteropathy at the molecular level."
explanation: "The authors' own summary of the link this edge draws."
- name: Altered Chaperone-Myosin Complex Dissociation
biological_scale: MOLECULAR
description: >-
The mechanism of the recurrent p.Leu237Pro allele, and the reason this entry
does not treat every variant as a null. The mutant protein still chaperones:
it prevents myosin aggregation and supports normal nonmuscle myosin II
filament formation. What it cannot do is let go. It forms atypically stable
oligomers that hold the chaperone-myosin complex together, and the trapped
myosin is therefore unavailable, so the cellular consequence converges on the
same trafficking failure as outright deficiency.
genetic_context:
variant_origin: GERMLINE
functional_impact_category: NEOMORPHIC
molecular_functions:
- preferred_term: availability of nonmuscle myosin II released from the chaperone
modifier: DECREASED
notes: >-
The molecular function here is deliberately unbound. An earlier revision
used GO:0017022 (myosin binding) with modifier DECREASED, which asserts the
opposite of what this node describes: binding is not reduced, it is
abnormally persistent, and what falls is the supply of myosin the complex
has released. GO has no term for the released-and-usable fraction, and
binding is the only nearby concept, so no term beats a term pointing the
wrong way. A reader querying for decreased myosin binding would have got
this node back and drawn the wrong conclusion from it.
evidence:
- reference: PMID:40125554
reference_title: "Altered chaperone-nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The UNC45A p.Leu237Pro mutant retained chaperone activity, prevented myosin aggregation, and supported proper nonmuscle myosin II (NMII) filament formation in patient fibroblasts and human osteosarcoma (U2OS) cells."
explanation: >-
Establishes that this allele is not a loss of chaperone activity, which is
what rules out folding it into the loss-of-function node.
- reference: PMID:40125554
reference_title: "Altered chaperone-nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "However, the mutant formed atypically stable oligomers and prevented chaperone-myosin complex dissociation, thereby inhibiting NMII functions."
explanation: "The positive mechanism: failure to release the client rather than failure to fold it."
downstream:
- target: Apical Trafficking and Recycling Endosome Failure
causal_link_type: DIRECT
description: >-
Despite the different molecular route, the cellular endpoint is the same as
in outright deficiency.
evidence:
- reference: PMID:40125554
reference_title: "Altered chaperone-nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Similar to biallelic UNC45A deficiency, this resulted in impaired intracellular trafficking, defective recycling, and abnormal retention of transferrin at various endocytic sites."
explanation: "States the convergence on the trafficking phenotype, which is exactly what this edge asserts."
- name: Bile Salt Export Pump Mislocalization
biological_scale: CELLULAR
conforms_to: "cholestatic_liver_injury#Impaired Bile Formation and Secretion"
description: >-
The hepatic arm, and the newest part of this mechanism. A patient liver biopsy
shows reduced UNC45A protein together with reduced expression and aberrant
localization of the bile salt export pump in hepatocytes. BSEP is the
canalicular exporter, so mislocalizing it is a failure of bile formation at
its first step - which matches the low-GGT biochemical picture these patients
have.
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
biological_processes:
- preferred_term: canalicular bile acid transport
modifier: DECREASED
term:
id: GO:0015722
label: canalicular bile acid transport
evidence:
- reference: PMID:41861679
reference_title: "Odevixibat treatment for recurrent cholestasis in a patient with biallelic UNC45A variants causing osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immunofluorescence microscopy of the liver specimen archived at age 10 showed reduced expression of the UNC45A protein and reduced expression and aberrant localization of the bile salt export pump (BSEP) in hepatocytes"
explanation: >-
Both halves of the claim in one patient specimen: the chaperone is reduced
and the transporter it should be helping to place is mislocalized. A single
biopsy, which is why this node is not stated more strongly.
downstream:
- target: Intrahepatic cholestasis
causal_link_type: DIRECT
- name: Apical Trafficking and Recycling Endosome Failure
biological_scale: CELLULAR
conforms_to: "enterocyte_polarity_trafficking_failure#Loss of Apical Delivery Machinery"
description: >-
RAB11A-positive recycling endosomes are mispositioned and apical transporters
do not reach the membrane. The enterocyte can no longer build or hold a
polarized absorptive surface. This is the module's trafficking arm entered one
step upstream of its canonical MYO5B lesion: here the motor is present but
unfolded rather than absent.
cell_types:
- preferred_term: enterocyte
term:
id: CL:0000584
label: enterocyte
cellular_components:
- preferred_term: recycling endosome
term:
id: GO:0055037
label: recycling endosome
biological_processes:
- preferred_term: apical protein localization
modifier: DECREASED
term:
id: GO:0045176
label: apical protein localization
evidence:
- reference: PMID:35575086
reference_title: "UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Patients and UNC45AKO 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli."
explanation: >-
The trafficking failure shown in patient-derived organoids as well as in the
engineered knockout, which is what makes it a patient phenotype and not only
a cell-line one.
- reference: PMID:35575086
reference_title: "UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Overall, lack of apical Na+ transporters and retention of CFTR at the apical pole of enterocytes suggest that the inability to absorb Na+ combined with active Cl– secretion may be the driving cause of diarrhea in UNC45A deficiency."
explanation: >-
Why the diarrhoea is secretory rather than only malabsorptive, which the
generic "apical transporter mislocalization" above does not convey. The
failure is selective: NHE3 and DRA do not reach the membrane while CFTR
does, so chloride secretion continues into a lumen from which sodium can
no longer be absorbed. That selectivity is also what makes congenital
chloride diarrhoea a plausible misdiagnosis - see the differential in the
diagnosis section.
downstream:
- target: Microvillus Inclusion Formation and Brush Border Loss
causal_link_type: DIRECT
- name: Microvillus Inclusion Formation and Brush Border Loss
biological_scale: TISSUE
description: >-
Microvilli are internalized into intracellular inclusions instead of being
presented apically, and the surviving brush border is sparse and disorganized.
Duodenal biopsies show villus atrophy without inflammation, which is the
finding that separates this from an immune enteropathy at the bench as well as
at the bedside. The same picture is present in zebrafish enterocytes, so it is
not an artefact of any one system.
cell_types:
- preferred_term: enterocyte
term:
id: CL:0000584
label: enterocyte
cellular_components:
- preferred_term: microvillus
term:
id: GO:0005902
label: microvillus
evidence:
- reference: PMID:35575086
reference_title: "UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "They all showed villus atrophy with no inflammation"
explanation: >-
Patient duodenal biopsy histology. The absence of inflammation is the point:
it excludes the immune enteropathies that otherwise present the same way.
- reference: PMID:35575086
reference_title: "UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish."
explanation: >-
Cross-species confirmation of the same subcellular lesion. Graded
MODEL_ORGANISM because the observation quoted is the zebrafish one, even
though the paper also reports human biopsies elsewhere.
downstream:
- target: Chronic diarrhea
causal_link_type: DIRECT
phenotypes:
- category: Gastrointestinal
name: Chronic diarrhea
description: >-
Congenital, intractable and feeding-independent. This is the manifestation
that drives intestinal failure and parenteral-nutrition dependence.
phenotype_term:
preferred_term: Chronic diarrhea
term:
id: HP:0002028
label: Chronic diarrhea
onset:
onset_category: CONGENITAL
frequency: VERY_FREQUENT
evidence:
- reference: PMID:29429573
reference_title: "Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility."
explanation: "The presenting phenotype in the original families, and one of the four organs the syndrome name records."
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The most common clinical symptoms of the reported O2HE patients were severe diarrhea (9/10), followed by neonatal cholestasis (8/10), and bone fracture and deafness were presented in six and four patients, respectively"
explanation: >-
The quantitative anchor for the VERY_FREQUENT band: 9 of the 10 patients in
the literature at the time of this review. It is also the most frequent of
the four defining features, which the syndrome name does not convey.
- category: Prenatal and Birth
name: Premature birth
description: >-
A third of the published cases were born preterm. The 2025 review raises
the possibility that UNC45A loss contributes to preterm birth itself rather
than prematurity being incidental, though it puts that no more strongly
than a suggestion.
phenotype_term:
preferred_term: Premature birth
term:
id: HP:0001622
label: Premature birth
frequency: FREQUENT
evidence:
- reference: PMID:41081434
reference_title: "A Case Report and Literature Review on Osteo-Oto-Hepato-Enteric Syndrome in Premature Infants Caused by UNC45A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Among the 12 published cases, four were premature, suggesting that UNC45A mutations may contribute to preterm birth and even recurrent miscarriage."
explanation: >-
Four of twelve sets the FREQUENT band. The same sentence carries the
authors' hypothesis about causation, which is theirs and is not asserted
by this entry - the phenotype record claims the association only.
- category: Gastrointestinal
name: Villous atrophy
phenotype_term:
preferred_term: Villous atrophy
term:
id: HP:0011473
label: Villous atrophy
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:35575086
reference_title: "UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "They all showed villus atrophy with no inflammation"
explanation: "Duodenal biopsy finding in the patients from whom biopsies were available."
- category: Hepatic
name: Intrahepatic cholestasis
phenotype_term:
preferred_term: Intrahepatic cholestasis
term:
id: HP:0001406
label: Intrahepatic cholestasis
frequency: VERY_FREQUENT
evidence:
- reference: PMID:41861679
reference_title: "Odevixibat treatment for recurrent cholestasis in a patient with biallelic UNC45A variants causing osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "O2HE is a rare, difficult to diagnose syndrome characterized by congenital cholestatic pruritus, diarrhea, sensorineural hearing loss and/or bone fragility."
explanation: >-
Records the cholestasis as a defining feature and adds pruritus, which is
the symptom that actually drives treatment in this patient.
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The most common clinical symptoms of the reported O2HE patients were severe diarrhea (9/10), followed by neonatal cholestasis (8/10), and bone fracture and deafness were presented in six and four patients, respectively"
explanation: >-
The quantitative anchor for the VERY_FREQUENT band: 8 of 10 patients in the
literature review, second only to the diarrhoea.
- category: Auditory
name: Sensorineural hearing impairment
description: >-
Present in a minority of reported patients on the counts available, but the
counts are not a settled answer: hearing loss was diagnosed at 5 years in
one patient and in the teens in another, so a cross-sectional tally of a
cohort that includes infants will undercount it.
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
frequency: FREQUENT
evidence:
- reference: PMID:29429573
reference_title: "Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility."
explanation: >-
One of the four defining organs. The quote says impaired hearing; the
sensorineural qualifier comes from the disease name and the later
literature rather than from this sentence.
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The most common clinical symptoms of the reported O2HE patients were severe diarrhea (9/10), followed by neonatal cholestasis (8/10), and bone fracture and deafness were presented in six and four patients, respectively"
explanation: >-
The count that sets the band. Four of ten is FREQUENT, not VERY_FREQUENT,
and this entry previously said VERY_FREQUENT on the strength of the feature
appearing in the syndrome name rather than on any denominator.
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Since some O2HE patients’ hearing loss was diagnosed in the late age, further hearing testing is necessary to determine the possible hearing impairment of the patient."
explanation: >-
Recorded alongside the count because it qualifies it. Two of the reported
patients were diagnosed late, so 4/10 is a floor rather than an estimate,
and the band should be read as the evidence available and not as a settled
penetrance.
- category: Skeletal
name: Pathologic fracture
description: Bone fragility, the "osteo" of the syndrome name.
phenotype_term:
preferred_term: bone fragility
term:
id: HP:0002756
label: Pathologic fracture
frequency: FREQUENT
evidence:
- reference: PMID:29429573
reference_title: "Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility."
explanation: >-
The skeletal phenotype as reported. The source says "bone fragility" without
specifying fracture counts or bone density, so the binding is the fracture
term and the free text keeps the source's own wording.
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The most common clinical symptoms of the reported O2HE patients were severe diarrhea (9/10), followed by neonatal cholestasis (8/10), and bone fracture and deafness were presented in six and four patients, respectively"
explanation: >-
The quantitative anchor for the FREQUENT band: six of ten patients. The
same review's table shows the fracture burden is not uniform either, running
from one fracture to twenty-three in individual patients.
- category: Neurologic
name: Mild intellectual disability
description: >-
Reported in some but not all patients. Not one of the four organs in the
syndrome name, and the source states it without a denominator.
phenotype_term:
preferred_term: Mild intellectual disability
term:
id: HP:0001256
label: Mild intellectual disability
frequency: OCCASIONAL
evidence:
- reference: PMID:40125554
reference_title: "Altered chaperone-nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mild intellectual disability and developmental delay occurred in some of the patients with O2HE syndrome."
explanation: >-
The only statement of this feature in the cited literature. "Some" without
a count is why the frequency band is OCCASIONAL rather than anything firmer.
genetic:
- name: UNC45A
gene_term:
preferred_term: UNC45A
term:
id: hgnc:30594
label: UNC45A
association: Causative
relationship_type: CAUSATIVE
notes: >-
Biallelic variants; 23 exons encoding a 944-residue protein with TPR, armadillo,
neck and UCS domains. Reported alleles include p.Arg241Ter and p.Asp484GlufsTer31
(no detectable protein), the missense alleles p.Thr230Arg, p.Leu237Pro, p.Glu728Lys
and p.Ala838Pro (protein expressed at wild-type levels but non-functional in
rescue), p.Val423Asp (destabilized), and the compound heterozygous p.Arg819Ter
with p.Leu237Pro in a Chinese neonate. Variants in genes previously associated
with microvillus inclusion disease - MYO5B, STX3, STXBP2 - were excluded in the
patients, which is what makes UNC45A a distinct cause rather than a modifier.
Two further points matter for interpreting a new variant. p.Leu237Pro is not a
null: it retains chaperone activity and fails by trapping its client, so it is
modelled as a separate NEOMORPHIC pathophysiology node rather than folded into
the loss-of-function one. And UNC45A is allelic to a second disease - a 5'-UTR
variant causes Aagenaes syndrome (lymphoedema cholestasis syndrome 1), which
shares the neonatal cholestasis but adds lymphoedema and is not this entity.
evidence:
- reference: PMID:29429573
reference_title: "Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder."
explanation: "The gene-disease assignment."
- reference: PMID:36587802
reference_title: "UNC45A-related osteo-oto-hepato-enteric syndrome in a Chinese neonate."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The gene detection results showed that the UNC45A gene of the newborn examined in the present study harbored the compound heterozygous variants p.Arg819Ter, and p.Leu237Pro; this was confirmed via Sanger sequencing."
explanation: "An independent case with a recurrent missense allele in trans with a nonsense allele."
- reference: PMID:40125554
reference_title: "Altered chaperone-nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In addition to facilitating various NMII-associated processes, UNC45A promotes the folding of myosin IB (MYO1B) and MYO5B, supporting their functions in vesicle trafficking"
explanation: >-
Names the client repertoire. Relevant to this record because it is why a
single gene produces a four-organ phenotype, and why MYO5B is one client
among several rather than the whole story.
- reference: PMID:39887522
reference_title: "A New Unc45a 5'utr Variant In Patients With Aagenaes Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The genetic basis for this syndrome was recently linked to a variant in the 5'-untranslated region (5'-UTR) of the UNC45A gene, located on chromosome 15q."
explanation: >-
Supports the allelic-disorder statement in the notes: a different class of
UNC45A variant produces Aagenaes syndrome, not this disease.
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "no obvious genotype and phonotype correlations were observed"
explanation: >-
The negative result on allele class. Quoted with the source's own
misspelling of "phenotype", which a snippet does not correct. Fifteen
variants across eleven patients and no correlation - which is why this
entry separates the alleles by mechanism in the notes rather than by
expected severity.
- name: MYO5B
gene_term:
preferred_term: MYO5B
term:
id: hgnc:7603
label: MYO5B
association: Mechanistic client, not a modifier of this disease
relationship_type: COOPERATING
notes: >-
MYO5B is recorded here because it is the UNC45A client whose depletion carries
the enteropathy, not because MYO5B variants modify this disease. No MYO5B
variant has been reported in a patient with osteootohepatoenteric syndrome; the
original series explicitly excluded MYO5B, STX3 and STXBP2 before landing on
UNC45A. Biallelic MYO5B loss causes microvillus inclusion disease, which is the
separate disease this one converges on mechanistically.
evidence:
- reference: PMID:35575086
reference_title: "UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45AKO Caco-2 cells."
explanation: >-
Establishes the client relationship. This is the only sense in which MYO5B
belongs in this entry, and the notes say so explicitly so the record is not
read as a second disease gene.
treatments:
- name: Parenteral nutrition
description: >-
The enteropathy is feeding-independent, so the absorptive deficit is bypassed
rather than corrected. This is supportive management of intestinal failure and
is inferred from the disease class rather than reported as an outcome in these
patients.
treatment_term:
preferred_term: total parenteral nutrition
term:
id: NCIT:C29484
label: Total Parenteral Nutrition
target_mechanisms:
- target: Microvillus Inclusion Formation and Brush Border Loss
description: Bypasses the lost absorptive surface; it does not restore it.
evidence:
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Parenteral nutrition and enteral nutrition were required to treat severe diarrhea."
explanation: >-
A statement of what the reported patients actually received, across the
published cohort rather than in one family.
notes: >-
An earlier revision of this entry said no cited paper stated a nutritional
management recommendation in a quotable form, and rested the treatment on
the mechanism instead. That was true only because the review that states it
had not been cited. What the quote establishes is still narrow: that
parenteral and enteral nutrition were required, not that either was
evaluated against an alternative. No treatment study exists for this
disease, and the dependence is reported as a feature of the course - most
of the cohort table's entries read "need TPN" - rather than as an outcome.
- name: Odevixibat
description: >-
An ileal bile acid transporter inhibitor, used off-label here for the
cholestatic pruritus. It is a rational target given the mechanism in this
entry - if canalicular export is failing, interrupting the enterohepatic
circulation lowers the bile acid load rather than trying to fix the pump - but
the evidence is one adult patient reported as a letter, and the same letter
says plainly that no cure or effective treatment exists for this disease.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: odevixibat
term:
id: CHEBI:757063
label: odevixibat
target_mechanisms:
- target: Bile Salt Export Pump Mislocalization
description: >-
Does not correct the mislocalization. It reduces the bile acid pool
presented to the failing canalicular step by blocking ileal reuptake.
target_phenotypes:
- preferred_term: Intrahepatic cholestasis
term:
id: HP:0001406
label: Intrahepatic cholestasis
evidence:
- reference: PMID:41861679
reference_title: "Odevixibat treatment for recurrent cholestasis in a patient with biallelic UNC45A variants causing osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we wish to report a case of osteo-oto-hepatic-enteric syndrome (O2HE), successfully treated with odevixibat."
explanation: >-
The single reported treatment response. Note the paper spells the syndrome
"osteo-oto-hepatic-enteric"; the quote preserves the source's spelling.
- reference: PMID:41861679
reference_title: "Odevixibat treatment for recurrent cholestasis in a patient with biallelic UNC45A variants causing osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There is no cure or effective treatment, and the pathogenic mechanisms are not known."
explanation: >-
Quoted deliberately alongside the response above. The same authors who
report the success state the general position, and an entry that recorded
only the first sentence would overstate the evidence.
- name: Ursodeoxycholic acid
description: >-
A bile acid used as first-line supportive therapy for intrahepatic
cholestasis generally, and the therapy the one reported patient who
recovered was on. It does not address the mislocalized export pump; it
shifts the composition of the circulating bile acid pool towards a less
cytotoxic species, so the hepatocyte tolerates the retained load better.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ursodeoxycholic acid
term:
id: CHEBI:9907
label: ursodeoxycholic acid
target_phenotypes:
- preferred_term: Intrahepatic cholestasis
term:
id: HP:0001406
label: Intrahepatic cholestasis
evidence:
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient was managed with ursodeoxycholic acid (UDCA)-based treatments, and the clinical symptoms and abnormal liver functions were significantly relieved."
explanation: >-
The only reported response. Note what the sentence does not say: the
patient also received fat-soluble vitamins, compound glycyrrhizin and
ademetionine, so "UDCA-based" is the authors' own hedge and no source
here separates the contribution of one agent from the others.
notes: >-
Deliberately not given a target_mechanisms link. Every mechanism node in
this entry is a trafficking or folding defect, and ursodeoxycholic acid
acts on none of them - it changes the bile acid pool the failing canalicular
step has to handle. Attaching it to Bile Salt Export Pump Mislocalization
would assert a mechanism of action the evidence does not carry, so the
treatment is linked to the phenotype it relieves instead.
- name: Cochlear device implantation
description: >-
Standard management for severe congenital sensorineural hearing loss. As with
the nutritional support, this is the management the phenotype implies and not
an outcome reported in these patients.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: cochlear device implantation
term:
id: NCIT:C15329
label: Surgical Procedure
qualifiers:
- predicate:
preferred_term: medical device
term:
id: NCIT:C16830
label: Medical Device
value:
preferred_term: cochlear implant
term:
id: NCIT:C157820
label: Cochlear Implant
target_phenotypes:
- preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
notes: >-
Also deliberately unevidenced for this disease. The term binding follows the
convention in CLAUDE.md: the action term is bound because TreatmentTerm is
rooted at Clinical Intervention or Procedure and the device term is not
reachable from there, with the device carried as a qualifier so it stays
queryable.
diagnosis:
- name: Duodenal biopsy with electron microscopy
description: >-
Villus atrophy without inflammation on light microscopy, and microvillus
inclusions with subapical vesicle accumulation on electron microscopy. The
finding is indistinguishable from microvillus inclusion disease, which is the
diagnostic trap: the histology names the mechanism, not the gene.
diagnosis_term:
preferred_term: duodenal biopsy
term:
id: NCIT:C15189
label: Biopsy Procedure
evidence:
- reference: PMID:35575086
reference_title: "UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "They all showed villus atrophy with no inflammation"
explanation: "The light-microscopy finding this biopsy detects."
- name: Molecular testing of UNC45A
description: >-
Sequencing is what distinguishes this from microvillus inclusion disease,
since the histology does not. Testing should follow exclusion of MYO5B, STX3
and STXBP2, which is the order the original series worked in.
diagnosis_term:
preferred_term: UNC45A gene sequencing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:36587802
reference_title: "UNC45A-related osteo-oto-hepato-enteric syndrome in a Chinese neonate."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The gene detection results showed that the UNC45A gene of the newborn examined in the present study harbored the compound heterozygous variants p.Arg819Ter, and p.Leu237Pro; this was confirmed via Sanger sequencing."
explanation: "Trio exome followed by Sanger confirmation, which is the diagnostic route in practice."
- name: Differentiation from congenital chloride diarrhoea
description: >-
The second diagnostic trap, and the more practical one. A neonate with
watery diarrhoea and polyhydramnios is worked up for congenital chloride
diarrhoea long before UNC45A is considered; one reported infant was
investigated as CCD twice, once on prenatal ultrasound and again after
birth. Stool and serum electrolytes are what separate them, since the
chloride-losing profile of CCD is absent here.
diagnosis_term:
preferred_term: stool and serum electrolyte measurement
term:
id: NCIT:C25294
label: Laboratory Procedure
evidence:
- reference: PMID:41081434
reference_title: "A Case Report and Literature Review on Osteo-Oto-Hepato-Enteric Syndrome in Premature Infants Caused by UNC45A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Due to limited previous reports and insufficient clinical understanding, misdiagnosis and missed diagnosis of this disease often occur, such as being misdiagnosed as congenital chloride diarrhea (CCD) for the similar intestinal symptom."
explanation: >-
Names the misdiagnosis explicitly and says why it happens - the
intestinal presentation is shared. That is what makes this a differential
worth curating rather than a coincidence of one case.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Roughly a dozen patients. Four in three families in the 2018 gene-discovery
paper, six in five families in the 2022 mechanistic study, and single
subsequent case reports, with twelve patients counted in the literature as of
2025. No prevalence or incidence estimate exists and none is attempted here.
evidence:
- reference: PMID:36587802
reference_title: "UNC45A-related osteo-oto-hepato-enteric syndrome in a Chinese neonate."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, to date, only 10 patients with this syndrome have been reported in 2 studies; therefore, there is still a lack of analysis regarding the correlation between disease phenotype and genotype."
explanation: >-
A published count as of 2023, and the authors' own statement that the series
is too small for genotype-phenotype analysis.
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, a total of 10 O2HE patients from eight families with UNC45A loss-of-function mutations were described in the literature"
explanation: >-
The same count with the family denominator, which is the more useful
figure for a recessive disease: ten patients from eight families means
the reports are mostly independent rather than mostly sibships.
- reference: PMID:41081434
reference_title: "A Case Report and Literature Review on Osteo-Oto-Hepato-Enteric Syndrome in Premature Infants Caused by UNC45A Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, only 12 cases of O2HE associated with loss‐of‐function UNC45A mutations have been reported (Table 2), with severe diarrhea being the most consistent feature, followed by neonatal cholestasis."
explanation: >-
The 2025 count, and the source for the twelve-patient figure in the notes
above. An earlier revision asserted that figure with only ten-patient
evidence beside it, which made the entry state a number it could not
show.
progression:
- phase: Intestinal failure and early mortality in the severe tail
notes: >-
The counterweight to the remission phase below, added because recording
only the remitting course overcorrected. In the p.Leu237Pro series one
patient required complete enterectomy and two died early. At the other end
of the same spectrum a patient reached 33 with relapsing cholestatic
pruritus rather than remission. Neither outcome is the rule; the point is
that the course runs from death in infancy to lifelong relapsing disease,
and an entry carrying only the mild end would mislead.
evidence:
- reference: PMID:40125554
reference_title: "Altered chaperone-nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of note, 1 patient underwent a complete enterectomy, whereas 2 cases resulted in early mortality."
explanation: >-
The severe outcomes in the homozygous p.Leu237Pro patients: one
enterectomy and two early deaths.
- reference: PMID:41861679
reference_title: "Odevixibat treatment for recurrent cholestasis in a patient with biallelic UNC45A variants causing osteo-oto-hepato-enteric syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 33-year-old male patient who has had episodes of unexplained severe pruritus, diarrhea and weight loss throughout his life."
explanation: >-
The persistent rather than fatal course, lifelong and still symptomatic
in adulthood. It is the third pattern, distinct from both remission and
early death.
- phase: Infantile remission of the hepatic and intestinal features
age_range: first year of life
notes: >-
Recorded because the entry otherwise reads as uniformly severe, which the
cohort does not support. Both defining visceral features have resolved in
reported patients: the literature table records cholestasis resolving at
2.5 and 3 years in three of the earlier patients, and the 2022 Chinese case
had diarrhoea and cholestasis both resolve by 6 months and was off all
drugs and growing normally at 1 year. This is a single reported course and
is not a prognosis; the same paper cautions that hearing loss and bone
fragility can declare themselves years later in patients whose gut and
liver have settled, so remission of two organs is not remission of the
disease.
evidence:
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In contrast, our patient only suffered with mild diarrhea (3–5 times/day) and recovered along with cholestasis relief at the age of 6 months."
explanation: >-
The remitting course in the mildest reported patient. Quoted verbatim,
including the source's en dash and the non-breaking space before
"months".
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our patient's clinical manifestations were less severe than those of the previous reported cases, which expands the clinical spectrum of O2HE."
explanation: >-
The authors' own framing, and the reason this is curated as a phase of
the disease rather than as a doubt about the diagnosis.
discussions:
- discussion_id: extraintestinal_mechanism_unknown
kind: KNOWLEDGE_GAP
prompt: >-
What is the mechanism of the bone, ear and liver involvement, and does any of
it run through myosin VB?
attaches_to:
- pathophysiology#Loss of UNC45A Myosin Co-Chaperone Function
- phenotypes#Pathologic fracture
- phenotypes#Sensorineural hearing impairment
- phenotypes#Intrahepatic cholestasis
rationale: >-
Two of the four organs in the syndrome name have no mechanism in this entry,
and that is a statement about the literature rather than about the curation.
The enteropathy is traced to myosin VB, and the liver now has an observation
of its own - reduced UNC45A with mislocalized BSEP in a patient biopsy -
though which myosin client carries that defect is unknown, which is why that
edge is indirect. For hearing and bone there is nothing: UNC45A folds
nonmuscle myosin II and myosin IB as well as myosin VB, and myosin motors are
central to both stereocilia function and osteoblast mechanics, so both are
reasonable starting hypotheses and neither has been tested. The entry records
them as phenotypes without upstream edges rather than inventing the chain.
evidence:
- reference: PMID:36699472
reference_title: "Case report: Osteo-oto-hepato-enteric syndrome caused by UNC45A deficiency."
supports: SUPPORT
evidence_source: OTHER
snippet: "UNC45A is required for proper folding of MYO15A. MYO15A is necessary for elongation and maintenance of inner ear hair cell stereocilia"
explanation: >-
The most specific candidate mechanism anyone has put in print for the
deafness, and the reason it is cited here rather than drawn as a
pathograph edge. It appears in a case report's discussion as an inference
from two separate literatures - that UNC45A folds MYO15A, and that MYO15A
maintains stereocilia - and neither of the three UNC45A papers cited in
this entry mentions MYO15A at all. evidence_source is OTHER because the
passage is a review argument, not a result. Naming the hypothesis is what
makes the gap testable; asserting it would make it look closed.
- discussion_id: allele_class_versus_severity
kind: KNOWLEDGE_GAP
prompt: >-
Do null alleles produce a more severe phenotype than the destabilizing missense
alleles?
attaches_to:
- pathophysiology#Biallelic UNC45A Loss of Function
rationale: >-
The reported alleles fall into distinguishable mechanistic classes - no protein,
protein present but non-functional, and protein destabilized - and one recurrent
missense allele (p.Leu237Pro) appears in more than one family. That is the
setup for a genotype-phenotype correlation, and the 2023 case report says
explicitly that the series is still too small to draw one. Whether the four
organs are involved in a fixed combination or vary with allele class is
therefore open.
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.
Self-review: consume PMID:36699472, frequency anchors, UDCA, band correction · 2026-09-11T14:00:14Z · View source
Self-review round performed while claude-review was unavailable (shared Claude account usage limit, resets 2026-09-12T20:00Z). I applied the two finding shapes the automated reviewer had raised on my other two PRs in this batch - an under-consumed deep-research source, and unquantified frequency bands - to this entry, and both were present. PMID:36699472 (Wang 2022, Front Genet) was named in the research report's source list and never cited. It is a case report with an eleven-patient literature review, and consuming it produced one correction and several additions. Correction: - Sensorineural hearing impairment was FREQUENCY VERY_FREQUENT on the strength of the feature appearing in the syndrome name, with no denominator. The review counts deafness in 4 of 10 patients, which is FREQUENT. Changed, with a second evidence item recording that two patients were diagnosed at 5 years and in the teens, so 4/10 is a floor rather than a penetrance estimate. Additions from the same source: - Quantitative frequency anchors for chronic diarrhoea (9/10), intrahepatic cholestasis (8/10) and pathologic fracture (6/10). - Ursodeoxycholic acid as a treatment - absent entirely, and the only agent in the entry with a documented clinical response. Deliberately given no target_mechanisms link, since it acts on none of the trafficking or folding nodes modelled here. - Parenteral nutrition had a note saying no cited paper stated a nutritional recommendation quotably. That was true only because the paper that states it had not been cited. Real evidence added and the note rewritten to say what the quote does and does not establish. - A progression block recording that the hepatic and intestinal features can remit in infancy, which the entry previously did not convey. - The negative genotype-phenotype result (15 variants, no correlation) on the UNC45A genetic record. - A family denominator on prevalence: ten patients from eight families. - The extraintestinal_mechanism_unknown discussion now names MYO15A as the one published candidate mechanism for the deafness, cited and graded OTHER, with an explanation of why it is cited in the gap rather than drawn as a pathograph edge: it is an inference in a case report's discussion, and none of the three UNC45A papers in this entry mentions MYO15A. Separate defect found by check-snippet-grading and fixed: one background sentence from PMID:35421597 was graded IN_VITRO in a pathophysiology node and HUMAN_CLINICAL in a phenotype. The grading unit is the passage, not the paper's overall design; the sentence is the paper's opening background statement, so the surviving use is graded OTHER to match its sibling quote, and the phenotype use was dropped as redundant. Validation: just validate-disorders (schema, terms, 45/45 snippets); check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-environmental-evidence, check-reference-titles, check-title-snippets, check-snippet-length, check-snippet-grading, check-folded-hyphens all clean; bulk OLS id/label comparison over 27 pairs, 0 mismatches.
Create: Osteootohepatoenteric_Syndrome · 2026-09-11T12:56:04Z · View source
De novo curation of osteootohepatoenteric syndrome (MONDO:0859164, UNC45A). DEEP-RESEARCH PROVIDER: the brief asked for perplexity. The Perplexity account's quota was exhausted mid-run (HTTP 401 insufficient_quota) after two of five reports had been produced. Rather than substituting a provider by hand, the run was re-issued with just dr_fallback='--fallback', which recorded the handover in the report's own frontmatter: requested_provider perplexity, fell_back true, provider_attempts listing perplexity (ProviderNotConfiguredError), falcon (ProviderAuthError 403) and claude_code (succeeded). The report is research/Osteootohepatoenteric_Syndrome-deep-research-claude_code.md (claude_code, 270.4 s, 20 citations), correctly renamed by the alignment step. Note on the fallback trigger: --fallback did NOT fire while PERPLEXITY_API_KEY was still set, because the configuration gate only checks that a key is present, not that it has quota. The run failed outright instead of handing over. Unsetting the key made the gate trip and the documented chain then worked as designed. The report changed the entry rather than confirming it, which is worth recording because the counterfactual is a materially worse record. Working from PubMed relevance-sorted search alone I had (a) no mechanism for the cholestasis and (b) all alleles modelled as loss of function. The report surfaced 2025 literature that supplies both corrections: PMID:41861679 shows reduced UNC45A with reduced and mislocalised bile salt export pump in a patient liver biopsy, giving the hepatic arm an observation of its own; and PMID:40125554 shows the recurrent p.Leu237Pro allele RETAINS chaperone activity and fails by forming atypically stable oligomers that will not release the folded myosin. That allele is therefore curated as a separate NEOMORPHIC pathophysiology node, not folded into the loss-of-function node. Report validation: reference_validation 12/12 resolved but quotes_valid 0 of 1 (PMC:PMC9868473 quote unsupported) and needs_review true; that reference is not cited here. term_validation 28/30 verified with 0 mislabelled and 2 obsolete (GO:0051082, GO:0032313) - markedly better than the two perplexity reports in this run, which mislabelled 13 of 31 and 13 of 47 respectively. No CURIE was taken from any report; all bindings were looked up against OLS in the same step they were written, and re-checked in bulk with a per-file id/label comparison before validation. Evidence: 34 snippets across 8 PMIDs, all exact-quote verified. One pathophysiology node conforms to enterocyte_polarity_trafficking_failure, entering through the trafficking arm (#Loss of Apical Delivery Machinery) and not the adhesion arm as that module's description requires; a second conforms to cholestatic_liver_injury#Impaired Bile Formation and Secretion. MYO5B is recorded in the genetic section with relationship_type COOPERATING and a note saying explicitly that it is the UNC45A client carrying the enteropathy and NOT a second disease gene or modifier - the original series excluded MYO5B, STX3 and STXBP2 before landing on UNC45A. Also recorded: UNC45A is allelic to Aagenaes syndrome via a 5'-UTR variant, which is a different disease. Two mistakes caught by validation: onset_category CONGENITAL_ONSET is not a permissible value (CONGENITAL is), and NCIT:C15189 was written with the label 'Biopsy' from recall rather than from a lookup - its canonical label is 'Biopsy Procedure'. The second is the failure mode CLAUDE.md warns about and is the second instance of it in this run; a bulk id/label checker was added to the loop afterwards. Validated with just validate (schema, terms, 34/34 snippets), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values.
Overview. Osteootohepatoenteric syndrome (OOHE, also styled O2HE or "osteo-oto-hepato-enteric syndrome") is an ultra-rare autosomal recessive multisystem disorder first delineated in 2018. It is defined by a variable combination of four core features reflected in its name: bone fragility (osteo-), sensorineural hearing loss (oto-), cholestasis (hepato-), and congenital/severe diarrhea (enteric-), sometimes accompanied by mild developmental delay and intellectual disability. It is caused by biallelic (compound heterozygous or homozygous) loss-of-function variants in UNC45A (Unc-45 Myosin Chaperone A), a myosin co-chaperone gene on chromosome 15q26.1 OMIM #619377; PMID:29429573.
Key identifiers: - OMIM: #619377 (phenotype), 611219 (UNC45A gene) - MONDO: MONDO:0859164 - MedGen: C5543557 (UID 1785846) - Gene:* UNC45A, HGNC gene ID 55898 approx. (NCBI Gene 55898), 15q26.1 - Orphanet-specific numeric entry was not retrievable through available search (not confirmed in this session — treat as unresolved rather than fabricate an ORPHA code)
Synonyms: O2HE syndrome; OOHE; osteo-oto-hepato-enteric syndrome; UNC45A-related disorder / UNC45A deficiency syndrome. A related but phenotypically distinct allelic entity — Aagenaes syndrome (cholestasis-lymphedema syndrome) presenting with neonatal cholestasis and lymphedema — has recently been linked to a UNC45A 5′-UTR regulatory variant (c.-88G>A) in combination with a loss-of-function allele, suggesting an expanding UNC45A-related allelic/phenotypic spectrum distinct from classic OOHE (PMID:39887522).
Evidence basis. Nearly all published data derive from individual case reports and small case series (aggregated literature review, not a large disease registry), supplemented by patient-derived cellular/organoid models and animal (zebrafish) studies. As of the most recent literature review (2025), 13 cases have been reported worldwide (PMC12516782), making this one of the rarest entries in the dismech Mendelian category.
Disease causal factor: Purely monogenic/genetic — biallelic loss-of-function (missense, nonsense, frameshift, small in-frame deletion, and splice) variants in UNC45A. No environmental, infectious, or mechanistic non-genetic cause has been described.
Genetic risk factors: - Compound heterozygosity is more common than homozygosity in reported cases (most patients are compound heterozygotes for two different UNC45A alleles) [PMID:29429573]. - Recurrent variant: c.710T>C (p.Leu237Pro), located in the central domain, is the most frequently reported pathogenic allele across unrelated families and has been mechanistically characterized as a distinctive "gain-of-interaction" rather than simple loss-of-function variant (PMC11949031; PMID:40125554). - Other reported variants: c.292C>T (p.Arg98Trp) (recurrent, found in ≥2 unrelated families — PMC9868473, PMC13019544); c.2534-2545del (p.Leu845-Met848del); c.592C>T (p.Gln198*); c.2455C>T (p.Arg819Ter); c.2581C>T; c.2633C>T; c.2734T>G; p.Val423Asp (destabilizing/proteasomal-degradation mechanism, PMC9218578). - Variants segregate with disease and are absent or present at very low frequency in gnomAD, consistent with a highly penetrant recessive Mendelian mechanism [OMIM #619377]. - No specific gnomAD constraint (pLI/LOEUF) figure for UNC45A could be independently confirmed from search results in this session; this should be verified directly against the gnomAD browser before citing a number.
Environmental/lifestyle risk factors: None established — this is a fully genetically determined disease with no known environmental trigger, though it may contribute to non-genetic risk of prematurity (4 of 12 reported cases were premature, suggesting UNC45A dysfunction may itself predispose to preterm birth) [PMC12516782].
Protective factors: None identified in the literature.
Gene-environment interactions: None reported; disease expression is governed by allele-specific molecular mechanism (see §6) rather than external modifiers, although intra-familial phenotypic discordance despite identical genotype has been documented (see §9, Penetrance/Expressivity), implying unidentified modifying factors (genetic or environmental) exist.
Phenotype frequencies below are drawn from the aggregated 13-case literature review (PMC12516782) unless otherwise cited.
| Phenotype | Frequency | Type | Onset | Suggested HPO term |
|---|---|---|---|---|
| Congenital/severe secretory diarrhea | 13/13 (100%) | GI symptom | Neonatal (within days of birth) | HP:0002014 Diarrhea / consider HP:0410030 Congenital diarrhea |
| Neonatal cholestasis / prolonged jaundice | 9/13 (69%) | Lab/clinical sign | Neonatal | HP:0200034 Cholestasis; HP:0006579 Prolonged neonatal jaundice |
| Bone fragility / recurrent fractures | 6/13 (46%) | Skeletal sign | Infancy–childhood | HP:0002659 Recurrent fractures; HP:0004349 Reduced bone mineral density |
| Sensorineural hearing loss | 6/13 (46%) | Sensory sign | Congenital/early | HP:0000407 Sensorineural hearing impairment |
| Premature delivery | 4/13 (31%) | Perinatal | Birth | HP:0001622 Premature birth |
| Villous atrophy / MVID-like enteropathy | Reported in multiple cases | Histopathology | Neonatal | HP:0011471 Villous atrophy |
| Hepatomegaly | Reported | Clinical sign | Infancy | HP:0002240 Hepatomegaly |
| Hepatic fibrosis | Reported (MedGen) | Histopathology | Variable | HP:0001395 Hepatic fibrosis |
| Mild developmental delay / intellectual disability | Subset of cases | Cognitive | Childhood | HP:0001263 Global developmental delay; HP:0001249 Intellectual disability |
| Osteoporosis (DEXA-confirmed) | Individual cases documented longitudinally (ages 14 and 25 in one patient) | Skeletal | Childhood onward | HP:0000939 Osteoporosis |
| Developmental dysplasia of the hip | Reported (MedGen) | Skeletal | Congenital | HP:0001385 Hip dysplasia |
| Pruritus (cholestasis-associated, episodic) | Reported in ≥1 case, severe (7-month episode) | Symptom | Variable | HP:0000989 Pruritus |
| Brain injury (neonatal) | Reported in neonatal cases | Neurological | Neonatal | Not further specified in sources retrieved |
| Recurrent miscarriage association | Suggested in literature review | Reproductive/perinatal | — | Not an HPO-codeable phenotype per se; notable epidemiological association |
Severity/progression: Highly variable — from near-complete clinical and biochemical recovery by 12 months in a milder Chinese case (normal hearing, no bone fragility) [PMC9868473] to severe secretory diarrhea requiring complete enterectomy and early mortality in 2 of 4 patients carrying the p.Leu237Pro variant in one cohort [PMC11949031]. Cholestasis can be relapsing/recurrent (benign recurrent intrahepatic cholestasis-like pattern) over decades, as documented in a 33-year-old patient followed from birth [PMC13019544].
Quality of life impact: Diarrhea and cholestasis drive substantial infancy/childhood morbidity (dehydration, growth failure, need for parenteral nutrition); hearing loss affects language development; bone fragility causes recurrent fractures affecting mobility. No formal EQ-5D/SF-36 data are available given the extreme rarity of the condition.
Causal gene: UNC45A (Unc-45 Myosin Chaperone A), OMIM *611219, chromosome 15q26.1. Suggest HGNC binding via lowercase hgnc: CURIE once confirmed via lookup (do not fabricate the numeric HGNC ID — verify via runoak/HGNC lookup before curation).
Variant classification and types (per ACMG/ClinVar framework, as reported in source papers): - Missense: p.Arg98Trp, p.Leu237Pro, p.Val423Asp - Nonsense/stop-gain: p.Gln198*, p.Arg819Ter - In-frame deletion: p.Leu845_Met848del (4 amino acids) - Regulatory (5′-UTR): c.-88G>A (associated with the related Aagenaes-syndrome-like phenotype, not classic OOHE) [PMID:39887522]
Zygosity: Predominantly compound heterozygous (biallelic, two different pathogenic variants); occasional homozygosity reported in consanguineous or founder contexts (not confirmed with a specific PMID in this session).
Functional consequence — allele-specific mechanisms (important for functional_impact_category curation):
1. Classic loss-of-function (e.g., nonsense/frameshift/most missense alleles): reduced UNC45A protein expression/stability, loss of chaperone activity for myosin folding [PMID:29429573].
2. p.Val423Asp: causes protein instability and proteasomal degradation rather than direct loss of chaperone catalytic function [PMC9218578].
3. p.Leu237Pro (c.710T>C): a distinctive non-classical, dominant-negative-like mechanism — the mutant retains chaperone/folding activity and still supports myosin filament assembly, but forms abnormally stable oligomeric chaperone-myosin complexes that fail to dissociate normally, thereby trapping and inhibiting nonmuscle myosin II (NMII) function and impairing transferrin/cargo recycling through endocytic compartments [PMC11949031]. This is a mechanistically distinct "trapping" gain-of-interaction phenotype layered on an overall loss-of-function disease, and is a strong candidate for functional_impact_category: DOMINANT_NEGATIVE at the GeneticContext level in a dismech curation, with careful attention to differentiating this from simple LOSS_OF_FUNCTION framing used for other alleles in the same gene.
Modifier genes: None formally established, though MYO5B is functionally (not genetically) linked — see mechanism section below — as UNC45A and MYO5B mutations converge on the same enterocyte apical-trafficking pathway causing overlapping enteropathy phenotypes between OOHE and microvillus inclusion disease (MVID) [PMC9218578].
Epigenetic information: No epigenetic mechanism has been reported for this disease.
Chromosomal abnormalities: None reported; disease is caused by point mutations/small indels, not large structural rearrangements.
Population frequency: All reported variants are rare or absent in gnomAD, consistent with a fully penetrant, ultra-rare recessive disorder; no specific allele frequency percentages could be confirmed from available sources in this session.
No environmental, toxin, occupational, dietary, or infectious contributing factors have been identified for OOHE — it is a fully monogenic disorder. The only quasi-environmental association reported is that UNC45A dysfunction itself may be a cause (not consequence) of prematurity and possibly recurrent miscarriage, based on the observation that 4 of 12 literature cases were born prematurely [PMC12516782] — this is a mechanistic/reproductive association rather than an external environmental risk factor and should not be modeled as an environmental: exposure entry.
Myosin Vb (MYO5B) and nonmuscle myosin II are the principal UNC45A "client" motor proteins; their misfolding/mistrafficking is the proximate lesion. Suggested GO terms: GO:0051082 (unfolded protein binding), GO:0051291 (protein heterooligomerization), GO:0016459 (myosin complex), GO:0090161 (Golgi ribbon formation — likely not directly relevant, verify), and most centrally GO:0032313 (regulation of Rab GTPase activity) and GO:0006892 (post-Golgi vesicle-mediated transport)/GO:1904776 (regulation of protein localization to apical plasma membrane) — these should be independently verified via OAK lookup before binding, per dismech's term-contract rules.
prevalence_class: BELOW_1_IN_1000000 / measure_type: CASES_IN_LITERATURE per dismech conventions, given the literature explicitly frames this as a cumulative case count rather than a population-based rate).Inheritance.penetrance or expressivity annotation.Laboratory tests: - Liver panel: elevated total and direct bilirubin (e.g., total bilirubin 136.75 μmol/L, direct bilirubin 104.38 μmol/L in one infant), elevated total bile acids (TBA up to 217.3 μmol/L), low GGT pattern of cholestasis (consistent with a BSEP-trafficking-type mechanism despite BSEP being genetically normal) [PMC9868473; PMC13019544]. - Stool studies: consistent with secretory diarrhea.
Imaging: - Abdominal ultrasound/imaging: hepatomegaly. - DEXA scan: reduced bone mineral density/osteoporosis, performed longitudinally in at least one patient (ages 14, 25).
Functional tests: - Auditory brainstem response (ABR): used to assess hearing (one case had normal ABR wave V threshold 25 dBHL; another had moderate bilateral sensorineural hearing loss confirmed via audiometry).
Biopsy/histopathology: - Intestinal biopsy: villous atrophy, microvillus inclusion disease-like features (sparse/disorganized/shortened microvilli, microvillus inclusions, enlarged lysosomes in villus enterocytes). - Liver biopsy: immunofluorescence showing reduced UNC45A protein expression and aberrant BSEP canalicular mislocalization [PMC13019544].
Genetic testing: - Whole exome sequencing (WES) is the diagnostic modality used in essentially all reported cases (identifying compound heterozygous UNC45A variants); given the syndrome's rarity and nonspecific overlapping presentation with other congenital diarrhea/cholestasis syndromes (e.g., MVID/MYO5B, other PFIC genes), a single-gene UNC45A panel is unlikely to be first-line — WES/WGS with a congenital-diarrhea or cholestasis gene panel is the practical approach. - No dedicated GTR/gene panel curated name could be confirmed from sources retrieved in this session.
Differential diagnosis: Microvillus inclusion disease (MYO5B, STX3, STXBP2 mutations) — overlapping enteropathy and even shared histopathology; other low-GGT progressive familial intrahepatic cholestasis syndromes (FIC1/ATP8B1, BSEP/ABCB11); congenital chloride/sodium diarrhea; other syndromic hearing-loss/bone-fragility overlap syndromes (e.g., osteogenesis imperfecta — noted as a differential in amedes-genetics resource). The related UNC45A allelic entity, Aagenaes/cholestasis-lymphedema syndrome, should also be distinguished.
Screening: No newborn screening or population carrier screening program exists for this ultra-rare condition.
No disease-specific approved therapy or standardized treatment guideline exists; management is supportive/symptomatic, targeting each organ system.
Pharmacotherapy for cholestasis:
- Ursodeoxycholic acid (UDCA), oral, e.g., 50 mg/day in an infant, used for cholestasis management [PMC9868473]. Suggested NCIT term: NCIT:C15986 (Pharmacotherapy) + therapeutic_agent CHEBI ursodeoxycholic acid (verify CURIE via lookup).
- Compound glycyrrhizin (IV) — reported to "relieve cholestasis by regulating bile acid transporters" [PMC9868473].
- Ademetionine 1,4-butanedisulfonate (S-adenosylmethionine) — hepatoprotective adjunct used alongside UDCA.
- Odevixibat — an ileal bile acid transporter (IBAT) inhibitor, used via compassionate use in a 31-year-old patient at 38.5 μg/kg/day; over 2.5 years of follow-up the patient experienced no further episodes of pruritus or weight loss, with sustained low bilirubin/bile acid levels — the first reported targeted pharmacologic intervention for recurrent UNC45A-associated cholestasis and notable because IBAT inhibitors are otherwise approved/studied for other genetic cholestatic diseases (e.g., PFIC, Alagille syndrome) [PMC13019544]. This represents a genuine therapeutic_modality: SMALL_MOLECULE candidate treatment worth curating with an NCIT/CHEBI binding for odevixibat if available.
- Fat-soluble vitamin supplementation (A, D, E, K) — standard supportive care for cholestasis-associated malabsorption.
Nutritional/supportive management for diarrhea:
- Combination of parenteral nutrition and enteral nutrition, individualized; some patients improve with oral formula feeding and gain weight over time [PMC12516782].
- In the most severe case, complete enterectomy was performed [PMC11949031] — an NCIT surgical-procedure term (NCIT:C15329 Surgical Procedure) would apply, with preferred_term specifying enterectomy.
Hearing loss management:
- Hearing aids — reported for moderate bilateral sensorineural hearing loss [PMC13019544]. Suggested NCIT device pattern per dismech convention: bind the clinical action term with a qualifiers device sub-binding rather than binding the device term directly to treatment_term (per the dismech Treatment Terms guidance on devices).
- No cochlear implantation has been specifically reported for this syndrome in the sources retrieved (unlike some other syndromic hearing-loss entries in the KB).
Bone fragility management: - No bisphosphonate use for OOHE specifically was confirmed in this session's searches (a bisphosphonate result returned was for an unrelated condition, MPS IVA) — do not assume bisphosphonate use without a direct primary-source citation; this is a plausible but currently unconfirmed treatment avenue for curation purposes.
Liver transplantation: - Reported as a rescue intervention in at least one sibling with severe liver failure, though specific to the related/overlapping Aagenaes-like phenotype rather than confirmed in classic OOHE cohorts [context from sibling-discordance search; PMID:39887522 general topic].
Experimental/investigational: No registered clinical trials specific to UNC45A/OOHE were identified in this session's searches; odevixibat use above was compassionate/off-label rather than a formal trial.
Treatment outcomes: Response to UDCA + supportive hepatoprotective regimen was associated with "complete clinical and biochemical recovery" at 12 months in a milder case [PMC9868473]. Odevixibat's 2.5-year efficacy signal (no pruritus/weight-loss recurrence) in a single adult patient is the strongest treatment-response data currently available, though it derives from a single case and should be treated as preliminary.
No primary, secondary, or tertiary prevention strategies exist beyond standard genetic counseling for known carrier couples (given full autosomal recessive inheritance) and, where a familial pathogenic variant is known, prenatal or preimplantation genetic testing could theoretically be offered — no specific literature on this practice for UNC45A/OOHE was identified in this session. No immunization, screening program, or public-health intervention is applicable to this monogenic disorder.
No naturally occurring UNC45A-deficient disease has been reported in non-human species (companion animals, livestock, or wildlife) in the sources retrieved — OMIA and veterinary literature searches were not performed in this session and should be checked separately before asserting a negative finding definitively.
Orthologous gene: UNC45A has zebrafish (unc45a) and Drosophila, C. elegans orthologs (the UNC-45/CRO1/She4p — "UCS" — protein family is deeply conserved from yeast to human); vertebrates have duplicated into two paralogs, UNC45A (general/non-muscle) and UNC45B (striated-muscle-specific).
Comparative biology: The UCS-domain myosin-chaperone function is evolutionarily ancient and highly conserved (from the yeast She4 protein through C. elegans UNC-45 to human UNC45A/B), supporting strong translational validity of model-organism mechanistic findings, though the disease-specific epithelial/hepatocyte trafficking phenotype appears to be a vertebrate/mammalian-relevant elaboration rather than a universally conserved disease mechanism.
Consistent with dismech's evidence-discipline requirements, the following should be independently verified via primary-source fetch and exact-quote extraction before being curated into a KB entry, since access restrictions in this session prevented full-text confirmation of several details: 1. The original 2018 Esteve et al. AJHG paper (PMID:29429573) abstract could not be directly fetched (ScienceDirect/PubMed blocked) — its exact founding cohort size, ages, and full phenotype table should be re-confirmed directly. 2. The OMIM entry and clinical synopsis (#619377) returned 403 errors and were reconstructed from MedGen/search-snippet cross-references only — the full OMIM clinical synopsis categories should be fetched directly (e.g., via an authenticated OMIM API key) before use as a curation source. 3. The CFTR-organoid paper (PMC12780477) content could not be extracted past a bot-check page; only its title/topic is confirmed. 4. No confirmed Orphanet (ORPHA) code was found for this entry in this session. 5. gnomAD constraint metrics (pLI/LOEUF) for UNC45A were not independently confirmed and should be pulled directly from the gnomAD browser.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 12 |
| Resolved | 12 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 0 |
| Quoted claims not found in source | 1 |
| References weighed for topical relevance | 12 |
| On topic | 8 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMC:PMC9868473 (abstract only): "relieve cholestasis by regulating bile acid transporters"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 30 |
| Resolved | 28 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 2 |
| Unverifiable | 0 |
These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0051082 (obsolete unfolded protein binding) (1 mention)GO:0032313 (GO_0032313) (1 mention) - replaced by GO:004308728 of 30 terms resolved to a current term; the rest could not be looked up either way.