Ornithine aminotransferase deficiency

Summary

Ornithine aminotransferase deficiency (MONDO:0009796) is a disease caused by OAT (GenCC Definitive), with 3 cohort genes and 5 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: OAT (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 666
• Phenotypes (HPO): 16
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Point prevalence	1-9 / 100 000	2	Finland	Not yet validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000529	Progressive visual loss	Very frequent (80-99%)
HP:0000533	Chorioretinal atrophy	Very frequent (80-99%)
HP:0000545	Myopia	Very frequent (80-99%)
HP:0012026	Hyperornithinemia	Very frequent (80-99%)
HP:0200065	Chorioretinal degeneration	Very frequent (80-99%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000523	Subcapsular cataract	Frequent (30-79%)
HP:0000618	Blindness	Frequent (30-79%)
HP:0001103	Abnormal macular morphology	Frequent (30-79%)
HP:0001133	Constriction of peripheral visual field	Frequent (30-79%)
HP:0003355	Aminoaciduria	Frequent (30-79%)
HP:0007675	Progressive night blindness	Frequent (30-79%)
HP:0040031	Chorioretinal hyperpigmentation	Frequent (30-79%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001595	Abnormality of the hair	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ornithine aminotransferase deficiency
Mondo ID	MONDO:0009796
MeSH	D015799
OMIM	258870
Orphanet	414
DOID	DOID:1415
NCIT	C84744
UMLS	C0018425
MedGen	6695
GARD	0006556
Is cancer (heuristic)	no

Also known as: Fuchs atrophia gyrata chorioideae et retinae · Fuchs gyrate atrophy · Fuchs gyrate atrophy of the choroid and retina · GACR · Girate atrophy of the retina · gyrate atrophy · gyrate atrophy of choroid and retina · gyrate atrophy of choroid and retina with or without ornithinemia · HOGA · hoga · hyperornithinemia · hyperornithinemia with gyrate atrophy of choroid and retina · hyperornithinemia-gyrate atrophy of choroid and retina syndrome · OAT deficiency · OKT deficiency · ornithine aminotransferase deficiency · ornithine ketoacid aminotransferase deficiency · Ornithinemia

Data availability: 666 ClinVar variants · 4 GenCC gene-disease records · 12 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › uveal disorder › optic choroid disorder › ornithine aminotransferase deficiency

Related subtypes (6): choroiditis, retinal dystrophies primarily involving Bruch’s membrane, choroidal sclerosis, central areolar choroidal dystrophy, choroideremia, choroid neoplasm

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

262 likely benign, 154 uncertain significance, 61 likely pathogenic, 57 pathogenic, 32 pathogenic/likely pathogenic, 17 conflicting classifications of pathogenicity, 16 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1402559	NM_000274.4(OAT):c.721_722dup (p.Asp242fs)	LOC121815974	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454173	NM_000274.4(OAT):c.680_702del (p.Ala226_Phe227insTer)	LOC121815974	Pathogenic	criteria provided, single submitter
160	NM_000274.4(OAT):c.734A>G (p.Tyr245Cys)	LOC121815974	Pathogenic	no assertion criteria provided
168	NM_000274.4(OAT):c.722C>T (p.Pro241Leu)	LOC121815974	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
169	NM_000274.4(OAT):c.749G>C (p.Arg250Pro)	LOC121815974	Pathogenic	no assertion criteria provided
181	NM_000274.4(OAT):c.677C>T (p.Ala226Val)	LOC121815974	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2133737	NM_000274.4(OAT):c.764_771+9delinsTTAGCTGTTTGTATCACACCA	LOC121815974	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2192304	NM_000274.4(OAT):c.697C>T (p.Gln233Ter)	LOC121815974	Pathogenic	criteria provided, single submitter
2849904	NM_000274.4(OAT):c.661_701del (p.Gln220_Asp221insTer)	LOC121815974	Pathogenic	criteria provided, single submitter
3075894	NM_000274.4(OAT):c.742G>T (p.Gly248Ter)	LOC121815974	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56135	NM_000274.4(OAT):c.748C>T (p.Arg250Ter)	LOC121815974	Pathogenic	criteria provided, multiple submitters, no conflicts
3244810	NC_000010.10:g.(?126100603)(126140009_?)del	NKX1-2	Pathogenic	criteria provided, single submitter
1072300	NM_000274.4(OAT):c.780del (p.Phe260fs)	OAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072790	NM_000274.4(OAT):c.1A>G (p.Met1Val)	OAT	Pathogenic	criteria provided, multiple submitters, no conflicts
1074082	NM_000274.4(OAT):c.1253_1260dup (p.Lys421delinsTrpTer)	OAT	Pathogenic	criteria provided, single submitter
1074423	NC_000010.10:g.(?126093995)(126100239_?)del	OAT	Pathogenic	criteria provided, single submitter
1075483	NM_000274.4(OAT):c.1150G>T (p.Glu384Ter)	OAT	Pathogenic	criteria provided, single submitter
1076328	NM_000274.4(OAT):c.576del (p.Ser193fs)	OAT	Pathogenic	criteria provided, single submitter
1213865	NM_000274.4(OAT):c.546_649-726del	OAT	Pathogenic	criteria provided, single submitter
1367020	NC_000010.10:g.(?126086501)(126086681_?)del	OAT	Pathogenic	criteria provided, single submitter
1376471	NM_000274.4(OAT):c.1159+1G>A	OAT	Pathogenic	criteria provided, single submitter
1393786	NM_000274.4(OAT):c.966del (p.Tyr323fs)	OAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1393887	NM_000274.4(OAT):c.515_516del (p.Phe172fs)	OAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1398334	NM_000274.4(OAT):c.881T>A (p.Leu294His)	OAT	Pathogenic	criteria provided, single submitter
1411610	NM_000274.4(OAT):c.1163G>A (p.Trp388Ter)	OAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1445996	NM_000274.4(OAT):c.1179_1182dup (p.Leu395fs)	OAT	Pathogenic	criteria provided, single submitter
1451166	NM_000274.4(OAT):c.896dup (p.Tyr299Ter)	OAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451560	NM_000274.4(OAT):c.304_305del (p.Lys102fs)	OAT	Pathogenic	criteria provided, single submitter
1452949	NM_000274.4(OAT):c.796C>T (p.Gln266Ter)	OAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455231	NM_000274.4(OAT):c.1001dup (p.Ala335fs)	OAT	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
OAT	Definitive	Autosomal recessive	ornithine aminotransferase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OAT	Orphanet:414	Gyrate atrophy of choroid and retina
RIMS1	Orphanet:1872	Cone rod dystrophy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OAT	HGNC:8091	ENSG00000065154	P04181	Ornithine aminotransferase, mitochondrial	gencc,clinvar
RIMS1	HGNC:17282	ENSG00000079841	Q86UR5	Regulating synaptic membrane exocytosis protein 1	clinvar
NKX1-2	HGNC:31652	ENSG00000229544	Q9UD57	NK1 transcription factor-related protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OAT	Ornithine aminotransferase, mitochondrial	Catalyzes the reversible interconversion of L-ornithine and 2-oxoglutarate to L-glutamate semialdehyde and L-glutamate.
RIMS1	Regulating synaptic membrane exocytosis protein 1	Rab effector involved in exocytosis.
NKX1-2	NK1 transcription factor-related protein 2	Transcriptional repressor.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	2	5.5×	0.081
Enzyme (other)	1	4.0×	0.230

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OAT	Enzyme (other)	yes	2.6.1.13	Aminotrans_3, Orn_aminotrans, PyrdxlP-dep_Trfase_major
RIMS1	Transcription factor	no		C2_dom, PDZ, Rab_BD
NKX1-2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
duodenum	1
jejunal mucosa	1
parotid gland	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
oocyte	1
primordial germ cell in gonad	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OAT	295	ubiquitous	marker	jejunal mucosa, parotid gland, duodenum
RIMS1	175	broad	marker	cerebellar cortex, cerebellar hemisphere, cerebellum
NKX1-2	53	tissue_specific	yes	secondary oocyte, primordial germ cell in gonad, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OAT	3,757
RIMS1	1,987
NKX1-2	472

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OAT	P04181	27
RIMS1	Q86UR5	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NKX1-2	Q9UD57	65.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glutamate and glutamine metabolism	1	407.9×	0.004	OAT
Acetylcholine Neurotransmitter Release Cycle	1	335.9×	0.004	RIMS1
Serotonin Neurotransmitter Release Cycle	1	317.2×	0.004	RIMS1
Norepinephrine Neurotransmitter Release Cycle	1	317.2×	0.004	RIMS1
GABA synthesis, release, reuptake and degradation	1	317.2×	0.004	RIMS1
Dopamine Neurotransmitter Release Cycle	1	248.3×	0.004	RIMS1
Glutamate Neurotransmitter Release Cycle	1	228.4×	0.004	RIMS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete L-arginine catabolic process to proline via ornithine	1	5617.3×	0.002	OAT
obsolete L-arginine catabolic process to L-glutamate	1	5617.3×	0.002	OAT
visual perception	2	53.0×	0.003	OAT, RIMS1
L-proline biosynthetic process	1	936.2×	0.004	OAT
acrosomal vesicle exocytosis	1	936.2×	0.004	RIMS1
positive regulation of inhibitory postsynaptic potential	1	936.2×	0.004	RIMS1
secretion	1	702.2×	0.004	RIMS1
obsolete synaptic vesicle docking	1	432.1×	0.006	RIMS1
calcium-ion regulated exocytosis	1	330.4×	0.006	RIMS1
regulated exocytosis	1	295.6×	0.006	RIMS1
synaptic vesicle priming	1	267.5×	0.006	RIMS1
synaptic vesicle exocytosis	1	255.3×	0.006	RIMS1
regulation of neurotransmitter secretion	1	255.3×	0.006	RIMS1
positive regulation of dendrite extension	1	244.2×	0.006	RIMS1
cell differentiation	2	19.4×	0.006	RIMS1, NKX1-2
membrane fusion	1	208.1×	0.007	RIMS1
positive regulation of excitatory postsynaptic potential	1	175.5×	0.007	RIMS1
regulation of synaptic vesicle exocytosis	1	151.8×	0.008	RIMS1
protein-containing complex assembly	1	38.0×	0.030	RIMS1
intracellular protein transport	1	21.6×	0.050	RIMS1
positive regulation of gene expression	1	12.9×	0.079	RIMS1
regulation of transcription by RNA polymerase II	1	3.9×	0.236	NKX1-2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
OAT	0	0
RIMS1	0	0
NKX1-2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
OAT	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
OAT	2.6.1.13	ornithine aminotransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	OAT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RIMS1, NKX1-2

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
OAT	6	—
RIMS1	0	—
NKX1-2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00001735	PHASE1	COMPLETED	Gene Therapy for Gyrate Atrophy
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05312736	Not specified	ACTIVE_NOT_RECRUITING	Gyrate Atrophy Ocular and Systemic Study
NCT00001166	Not specified	COMPLETED	Gyrate Atrophy of the Choroid and Retina