OPA1-related optic atrophy with or without extraocular features

Summary

OPA1-related optic atrophy with or without extraocular features (MONDO:0800181) is a disease caused by OPA1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: OPA1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	OPA1-related optic atrophy with or without extraocular features
Mondo ID	MONDO:0800181
GARD	0026472
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › OPA1-related optic atrophy with or without extraocular features

Related subtypes (13): oxoglutaricaciduria, multiple acyl-CoA dehydrogenase deficiency, inborn mitochondrial myopathy, HSD10 mitochondrial disease, histiocytoid cardiomyopathy, hypotonia-cystinuria syndrome, fumaric aciduria, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, mitochondrial pyruvate carrier deficiency, mitochondrial oxidative phosphorylation disorder, mitochondrial membrane transport disorder, inherited lipoic acid biosynthesis defect, pyruvate dehydrogenase deficiency

Subtypes (1): Behr syndrome

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

5 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3777025	GRCh38/hg38 3q29(chr3:193610482-193623779)x1	OPA1	Pathogenic	criteria provided, single submitter
419963	NM_130837.3(OPA1):c.959_962del (p.Ile320fs)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
5085	NM_130837.3(OPA1):c.1261C>T (p.Arg421Ter)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1376014	NM_130837.3(OPA1):c.3032T>C (p.Leu1011Pro)	OPA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2580214	NM_130837.3(OPA1):c.364T>C (p.Trp122Arg)	OPA1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 8 · 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
MED12	Definitive	Autosomal dominant	autosomal dominant optic atrophy, classic form	21
OPA1	Definitive	Autosomal dominant	autosomal dominant optic atrophy, classic form	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1
OPA1	Orphanet:1215	Autosomal dominant optic atrophy plus syndrome
OPA1	Orphanet:1239	Behr syndrome
OPA1	Orphanet:98673	Autosomal dominant optic atrophy, classic form

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	gencc,clinvar
OPA1	HGNC:8140	ENSG00000198836	O60313	Dynamin-like GTPase OPA1, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
OPA1	Dynamin-like GTPase OPA1, mitochondrial	Dynamin-related GTPase that is essential for normal mitochondrial morphology by mediating fusion of the mitochondrial inner membranes, regulating cristae morphology and maintaining respiratory chain function.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
OPA1	Enzyme (other)	yes	3.6.5.5	Dynamin_GTPase, Dynamin, P-loop_NTPase

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left ovary	1
right adrenal gland	1
right adrenal gland cortex	1
adrenal tissue	1
calcaneal tendon	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
OPA1	288	ubiquitous	marker	adrenal tissue, calcaneal tendon, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MED12	3,322
OPA1	2,630

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OPA1	O60313	11
MED12	Q93074	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 2 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
Regulation of Apoptosis	1	951.7×	0.023	OPA1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.038	MED12
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.038	MED12
Respiratory Syncytial Virus Infection Pathway	1	98.5×	0.038	MED12
RSV-host interactions	1	78.2×	0.038	MED12
Adipogenesis	1	78.2×	0.038	MED12
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.038	MED12
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.038	MED12
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.038	MED12
Mitochondrial protein degradation	1	57.1×	0.038	OPA1
PPARA activates gene expression	1	47.2×	0.042	MED12
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.044	MED12
Epigenetic regulation of gene expression	1	35.7×	0.047	MED12
Metabolism of lipids	1	15.8×	0.094	MED12
Viral Infection Pathways	1	15.4×	0.094	MED12
Infectious disease	1	12.4×	0.109	MED12
RNA Polymerase II Transcription	1	11.3×	0.112	MED12
Gene expression (Transcription)	1	8.9×	0.133	MED12
Generic Transcription Pathway	1	7.5×	0.147	MED12
Developmental Biology	1	7.2×	0.147	MED12
Disease	1	6.5×	0.154	MED12
Metabolism	1	5.8×	0.165	MED12

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
neural tube closure	2	187.2×	1e-03	MED12, OPA1
mitochondrial inner membrane fusion	1	8426.0×	0.002	OPA1
axis elongation involved in somitogenesis	1	2808.7×	0.003	MED12
membrane tubulation	1	2808.7×	0.003	OPA1
positive regulation of T-helper 17 cell lineage commitment	1	1053.2×	0.005	OPA1
embryonic neurocranium morphogenesis	1	936.2×	0.005	MED12
peroxisome fission	1	766.0×	0.005	OPA1
axonal transport of mitochondrion	1	702.2×	0.005	OPA1
GTP metabolic process	1	561.7×	0.005	OPA1
mitochondrial fission	1	526.6×	0.005	OPA1
Schwann cell development	1	526.6×	0.005	MED12
cristae formation	1	526.6×	0.005	OPA1
inner mitochondrial membrane organization	1	421.3×	0.005	OPA1
mitochondrial fusion	1	421.3×	0.005	OPA1
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1	421.3×	0.005	OPA1
negative regulation of release of cytochrome c from mitochondria	1	401.2×	0.005	OPA1
embryonic brain development	1	401.2×	0.005	MED12
post-anal tail morphogenesis	1	366.4×	0.005	MED12
protein complex oligomerization	1	337.0×	0.005	OPA1
endoderm development	1	312.1×	0.005	MED12
oligodendrocyte development	1	300.9×	0.005	MED12
positive regulation of interleukin-17 production	1	300.9×	0.005	OPA1
spinal cord development	1	255.3×	0.006	MED12
Wnt signaling pathway, planar cell polarity pathway	1	227.7×	0.006	MED12
cellular senescence	1	147.8×	0.009	OPA1
positive regulation of transcription initiation by RNA polymerase II	1	135.9×	0.010	MED12
somatic stem cell population maintenance	1	123.9×	0.010	MED12
mitochondrion organization	1	75.9×	0.016	OPA1
visual perception	1	39.8×	0.029	OPA1
heart development	1	39.4×	0.029	MED12

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
OPA1	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
OPA1	2	4
MED12	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	OPA1
TIVANTINIB	3	OPA1
MOLIBRESIB	2	MED12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MED12	6	Binding:6
OPA1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
OPA1	3.6.5.5	dynamin GTPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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.

Compound	Max phase	Cohort target (bioactivity)
MOMELOTINIB	4	OPA1
TIVANTINIB	3	OPA1
MOLIBRESIB	2	MED12

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	OPA1
B	Phased (≥1) drug, not yet approved	1	MED12
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.