OPA1

Summary

OPA1 (OPA1 mitochondrial dynamin like GTPase, HGNC:8140) is a protein-coding gene on chromosome 3q29, encoding Dynamin-like GTPase OPA1, mitochondrial (O60313). 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. It is a selective cancer dependency (DepMap: 57.7% of cell lines).

The protein encoded by this gene is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. The encoded protein localizes to the inner mitochondrial membrane and helps regulate mitochondrial stability and energy output. This protein also sequesters cytochrome c. Mutations in this gene have been associated with optic atrophy type 1, which is a dominantly inherited optic neuropathy resulting in progressive loss of visual acuity, leading in many cases to legal blindness.

Source: NCBI Gene 4976 — RefSeq curated summary.

At a glance

• Gene–disease (curated): OPA1-related optic atrophy with or without extraocular features (Definitive, ClinGen) — +7 more curated relationships
• Clinical variants (ClinVar): 1,753 total — 258 pathogenic, 93 likely-pathogenic
• Phenotypes (HPO): 2
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 57.7% of screened cell lines
• MANE Select transcript: NM_130837

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8140
Approved symbol	OPA1
Name	OPA1 mitochondrial dynamin like GTPase
Location	3q29
Locus type	gene with protein product
Status	Approved
Aliases	NTG, KIAA0567, FLJ12460, NPG, MGM1
Ensembl gene	ENSG00000198836
Ensembl biotype	protein_coding
OMIM	605290
Entrez	4976

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 29 protein_coding, 12 nonsense_mediated_decay, 6 retained_intron

ENST00000361150, ENST00000361510, ENST00000361715, ENST00000361828, ENST00000361908, ENST00000392436, ENST00000392437, ENST00000419435, ENST00000429164, ENST00000434811, ENST00000445863, ENST00000475899, ENST00000482865, ENST00000483516, ENST00000495261, ENST00000495476, ENST00000497189, ENST00000642289, ENST00000642445, ENST00000642593, ENST00000643329, ENST00000643737, ENST00000644595, ENST00000644629, ENST00000644841, ENST00000644959, ENST00000645553, ENST00000646085, ENST00000646277, ENST00000646544, ENST00000646699, ENST00000646793, ENST00000890752, ENST00000890753, ENST00000890754, ENST00000890755, ENST00000890756, ENST00000890757, ENST00000925500, ENST00000968579, ENST00000968580, ENST00000968581, ENST00000968582, ENST00000968583, ENST00000968584, ENST00000968585, ENST00000968586

RefSeq mRNA: 10 — MANE Select: NM_130837 NM_001354663, NM_001354664, NM_015560, NM_130831, NM_130832, NM_130833, NM_130834, NM_130835, NM_130836, NM_130837

CCDS: CCDS33917, CCDS43186, CCDS87183

Canonical transcript exons

ENST00000361510 — 31 exons

Exon	Start	End
ENSE00000924378	193643975	193644105
ENSE00000924379	193645553	193645625
ENSE00000924382	193648070	193648134
ENSE00000924383	193648795	193648871
ENSE00000924387	193659482	193659561
ENSE00000968966	193664880	193664996
ENSE00000968967	193666296	193666389
ENSE00000968968	193667170	193667280
ENSE00001149527	193662822	193662962
ENSE00001190570	193617784	193617837
ENSE00001190660	193626092	193626202
ENSE00001306402	193692063	193692132
ENSE00001887578	193694606	193697811
ENSE00003497338	193658887	193658995
ENSE00003498919	193657080	193657232
ENSE00003526144	193642765	193642845
ENSE00003534792	193615674	193615770
ENSE00003540008	193617178	193617285
ENSE00003549149	193643528	193643627
ENSE00003554467	193642975	193643049
ENSE00003558232	193618869	193618936
ENSE00003604184	193637952	193638065
ENSE00003628941	193654862	193655027
ENSE00003630986	193614723	193615041
ENSE00003646500	193637195	193637281
ENSE00003648145	193645728	193645800
ENSE00003656319	193631612	193631665
ENSE00003682287	193635418	193635522
ENSE00003684180	193643373	193643444
ENSE00003687933	193647065	193647180
ENSE00003909468	193593208	193593409

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 97.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.0919 / max 513.3541, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40616	45.5494	1824
40617	9.6345	1761
40615	2.7121	1295
40614	2.6187	1193
40613	1.0795	571
40618	0.4976	287

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	97.66	gold quality
calcaneal tendon	UBERON:0003701	96.91	gold quality
endothelial cell	CL:0000115	96.79	gold quality
secondary oocyte	CL:0000655	95.51	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.48	gold quality
cortical plate	UBERON:0005343	94.47	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.40	gold quality
middle temporal gyrus	UBERON:0002771	94.35	gold quality
heart right ventricle	UBERON:0002080	94.25	gold quality
monocyte	CL:0000576	93.97	gold quality
mononuclear cell	CL:0000842	93.81	gold quality
rectum	UBERON:0001052	93.62	gold quality
superior frontal gyrus	UBERON:0002661	93.33	gold quality
left ventricle myocardium	UBERON:0006566	93.29	gold quality
leukocyte	CL:0000738	93.25	gold quality
tibialis anterior	UBERON:0001385	93.20	gold quality
islet of Langerhans	UBERON:0000006	92.84	gold quality
ventricular zone	UBERON:0003053	92.84	gold quality
prefrontal cortex	UBERON:0000451	92.77	gold quality
muscle of leg	UBERON:0001383	92.76	gold quality
gastrocnemius	UBERON:0001388	92.67	gold quality
entorhinal cortex	UBERON:0002728	92.42	gold quality
postcentral gyrus	UBERON:0002581	92.38	gold quality
myocardium	UBERON:0002349	92.19	gold quality
ganglionic eminence	UBERON:0004023	92.16	gold quality
germinal epithelium of ovary	UBERON:0001304	92.09	gold quality
substantia nigra pars compacta	UBERON:0001965	92.03	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.02	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.96	gold quality
lateral globus pallidus	UBERON:0002476	91.95	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.56
E-MTAB-10042	no	83.79

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IKBKB, IKBKG, STOML2

miRNA regulators (miRDB)

130 targeting OPA1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-381-3P	99.93	71.87	2854

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 57.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• polymorphism is a marker for normal tension glaucoma (PMID:11810296)
• This study describes 14 novel mutations in the OPA1 gene in patients with autosomal dominant optic atrophy (PMID:12036970)
• Investigating the association between OPA1 polymorphisms and glaucoma: comparison between normal tension and high tension primary open angle glaucoma (PMID:12073024)
• OPA1 is anchored to the mitochondrial inner membrane facing the inter-membrane space. (PMID:12123827)
• Deletion of the OPA1 gene in a dominant optic atrophy family provides evidence that haploinsufficiency is the cause of disease. (PMID:12161614)
• Differential sublocalization of OPA1 isoforms in mitochondria. (PMID:12504110)
• involvement in the cytochrome c sequestration and might be a target for mitochondrial apoptotic effectors (PMID:12509422)
• Mutations of the OPA1 gene may contribute to the development of optic nerve atrophy in Japanese cases of optic atrophy. (PMID:12566046)
• The mutations (Glu347Stop and Arg366Stop) of the OPA1 gene are involved in the pathogenesis of bilateral optic atrophy in Japanese patients. (PMID:12842213)
• No association was found with changes in the OPA1 gene. (PMID:14516807)
• We have refined the previously reported association between OPA1 sequence changes and NTG by identifying a specific CC genotype at position +32 in IVS8 of the OPA1 gene that acts as a marker for NTG. (PMID:14551537)
• Mutation in the OPA1 gene is associated with dominant optic nerve atrophy (PMID:14566653)
• The R445H mutation in OPA1 might be the cause of the association between dominant optic atrophy and moderate deafness, a phenotype that may be currently underdiagnosed. (PMID:14644237)
• Mgm1/OPA1 is localized to the mitochondrial intermembrane space, where it is tightly bound to the outer surface of the inner membrane. Changes in mitochondria caused by overexpression of wild type or mutant forms or loss of protein are described. (PMID:14970223)
• Fis1, Drp1, and Opa1 have roles in apoptosis (PMID:15356267)
• This study used phosphorus magnetic resonance spectroscopy to assess calf muscle oxidative metabolism in six patients from two unrelated families carrying the c.2708-2711delTTAG deletion in exon 27 of the OPA1 gene. (PMID:15505825)
• This study describes a mutation in OPA1 causing a unique syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia. (PMID:15531309)
• These results in Koreans do not support results in Caucasians and indicate that ethnic differences may exist in association between polymorphisms in OPA1 gene and normal-tension glaucoma. (PMID:15534475)
• Linked to dominant optic atrophy on chromosome 3. (PMID:15635063)
• OPA1 expression in somata and dendrites of neurons of the layers II-VI of the motor cortex and frontal brain. In the cerebellar cortex, OPA1 expression was detected in the Purkinje cell layer, in the granule cell layer and in the molecular layer. (PMID:15700187)
• We identified a novel heterozygous G to A mutation at position +1 of intron 20 (g.IVS20+1G–>A) in both patients. (PMID:16006781)
• Optic atrophy and negative electroretinogram in a patient associated with a novel OPA1 mutation. (PMID:16021496)
• OPA1 has a role in release of cytochrome c and subsequent mitochondrial fragmentation during apoptosis (PMID:16115883)
• This study establishes a firm causal relationship between the Arg455His mutation, optic atrophy, and associated hearing loss. (PMID:16158427)
• The heterozygous R445H mutation in OPA1 was found in five patients with optic atrophy and deafness (PMID:16240368)
• Identification and cDNA analysis of four intronic and three exonic OPA1 gene mutations that cause a variety of splicing defects. (PMID:16323009)
• A novel mutation producing premature termination codon(R312X) at the OPA1 gene causes autosomal dominant optic atrophy (PMID:16331355)
• Overall, our results support haploinsufficiency as a genetic mechanism in OPA1-positive cases and also suggest that mtDNA genetic background may influence disease expression in a subset of cases. (PMID:16617242)
• REVIEW: the function of OPA1, mutations in which cause optic atrophy, with respect to the underlying pathophysiological processes (PMID:16737747)
• Not sufficient evidence to support association of single nucleotide polymorphisms evaluated in OPA1 with primary open-angle glaucoma /intraocular pressure or normal tension glaucoma in African-Caribbean population of Barbados, West Indies. (PMID:16785854)
• mitochondrial fragmentation correlates with processing of large isoforms of OPA1 (PMID:17003040)
• Our study provides evidence of the apparent value of molecular genetic analysis of OPA1 gene as predictive DNA testing, although the exact risk and benefit of this type of analysis awaits further study. (PMID:17016536)
• The intramitochondrial dynamin OPA1 exists as eight isoforms resulting from the alternate splicing combinations of exons (Ex) 4, 4b and 5b. Here it is showed that Ex4 confers in the fusion of the mitochondrial network. (PMID:17024226)
• The OPA1 IVS 8 +32 T/C polymorphism is associated with normal tension glaucoma, and may be used as a marker for this disease association. (PMID:17188046)
• A novel mutation, c.2848_2849delGA in OPA1, was identified in a Chinese family with (autosomal dominant optic atrophy) ADOA. This mutation is associated with hearing loss, but likely not high myopia. (PMID:17188070)
• OPA1 mutations were identified in 11/17 (65%) of the ADOA (autosomal dominant optic atrophy) pedigrees in this study. (PMID:17306754)
• Novel mutation of the OPA1 gene with a clinical phenotype of isolated optic atrophy. (PMID:17318099)
• The OPA1 mutation may be correlated with slow progression of autosomal dominant optic atrophy (DOA), and with phenotypic variations within the family (PMID:17415700)
• hFis1 and OPA1 modulate cellular senescence (PMID:17545159)
• A novel mutation of the OPA1 gene was detected in a Japanese patient with autosomal dominant optic atrophy (ADOA) (PMID:17579882)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	opa1	ENSDARG00000070801
mus_musculus	Opa1	ENSMUSG00000038084
rattus_norvegicus	Opa1	ENSRNOG00000001717
drosophila_melanogaster	Opa1	FBGN0261276
caenorhabditis_elegans		WBGENE00001134

Paralogs (6): DNM2 (ENSG00000079805), DNM1L (ENSG00000087470), DNM1 (ENSG00000106976), MX1 (ENSG00000157601), MX2 (ENSG00000183486), DNM3 (ENSG00000197959)

Protein

Protein identifiers

Dynamin-like GTPase OPA1, mitochondrial — O60313 (reviewed: O60313)

Alternative names: Optic atrophy protein 1

All UniProt accessions (19): O60313, A0A2R8Y3X5, A0A2R8Y4G4, A0A2R8Y4Q3, A0A2R8Y514, A0A2R8Y5E2, A0A2R8Y5G3, A0A2R8YD53, A0A2R8YDM2, A0A2R8YE54, A0A2R8YE78, A0A2R8YFD1, A0A2R8YGE5, C9JMB8, C9JY58, E5KLJ9, H7C141, H7C321, H7C3G2

UniProt curated annotations — full annotation on UniProt →

Function. 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. Exists in two forms: the transmembrane, long form (Dynamin-like GTPase OPA1, long form; L-OPA1), which is tethered to the inner mitochondrial membrane, and the short soluble form (Dynamin-like GTPase OPA1, short form; S-OPA1), which results from proteolytic cleavage and localizes in the intermembrane space. Both forms (L-OPA1 and S-OPA1) cooperate to catalyze the fusion of the mitochondrial inner membrane. The equilibrium between L-OPA1 and S-OPA1 is essential: excess levels of S-OPA1, produced by cleavage by OMA1 following loss of mitochondrial membrane potential, lead to an impaired equilibrium between L-OPA1 and S-OPA1, inhibiting mitochondrial fusion. The balance between L-OPA1 and S-OPA1 also influences cristae shape and morphology. Involved in remodeling cristae and the release of cytochrome c during apoptosis. Proteolytic processing by PARL in response to intrinsic apoptotic signals may lead to disassembly of OPA1 oligomers and release of the caspase activator cytochrome C (CYCS) into the mitochondrial intermembrane space. Acts as a regulator of T-helper Th17 cells, which are characterized by cells with fused mitochondria with tight cristae, by mediating mitochondrial membrane remodeling: OPA1 is required for interleukin-17 (IL-17) production. Its role in mitochondrial morphology is required for mitochondrial genome maintenance. Constitutes the transmembrane long form (L-OPA1) that plays a central role in mitochondrial inner membrane fusion and cristae morphology. L-OPA1 and the soluble short form (S-OPA1) form higher-order helical assemblies that coordinate the fusion of mitochondrial inner membranes. Inner membrane-anchored L-OPA1 molecules initiate membrane remodeling by recruiting soluble S-OPA1 to rapidly polymerize into a flexible cylindrical scaffold encaging the mitochondrial inner membrane. Once at the membrane surface, the formation of S-OPA1 helices induce bilayer curvature. OPA1 dimerization through the paddle region, which inserts into cardiolipin-containing membrane, promotes GTP hydrolysis and the helical assembly of a flexible OPA1 lattice on the membrane, which drives membrane curvature and mitochondrial fusion. Plays a role in the maintenance and remodeling of mitochondrial cristae, some invaginations of the mitochondrial inner membrane that provide an increase in the surface area. Probably acts by forming helical filaments at the inside of inner membrane tubes with the shape and dimensions of crista junctions. The equilibrium between L-OPA1 and S-OPA1 influences cristae shape and morphology: increased L-OPA1 levels promote cristae stacking and elongated mitochondria, while increased S-OPA1 levels correlated with irregular cristae packing and round mitochondria shape. Constitutes the soluble short form (S-OPA1) generated by cleavage by OMA1, which plays a central role in mitochondrial inner membrane fusion and cristae morphology. The transmembrane long form (L-OPA1) and the S-OPA1 form higher-order helical assemblies that coordinate the fusion of mitochondrial inner membranes. Inner membrane-anchored L-OPA1 molecules initiate membrane remodeling by recruiting soluble S-OPA1 to rapidly polymerize into a flexible cylindrical scaffold encaging the mitochondrial inner membrane. Once at the membrane surface, the formation of S-OPA1 helices induce bilayer curvature. OPA1 dimerization through the paddle region, which inserts into cardiolipin-containing membrane, promotes GTP hydrolysis and the helical assembly of a flexible OPA1 lattice on the membrane, which drives membrane curvature and mitochondrial fusion. Excess levels of S-OPA1 produced by cleavage by OMA1 following stress conditions that induce loss of mitochondrial membrane potential, lead to an impaired equilibrium between L-OPA1 and S-OPA1, thereby inhibiting mitochondrial fusion. Involved in mitochondrial safeguard in response to transient mitochondrial membrane depolarization by mediating flickering: cleavage by OMA1 leads to excess production of S-OPA1, preventing mitochondrial hyperfusion. Plays a role in the maintenance and remodeling of mitochondrial cristae, some invaginations of the mitochondrial inner membrane that provide an increase in the surface area. Probably acts by forming helical filaments at the inside of inner membrane tubes with the shape and dimensions of crista junctions. The equilibrium between L-OPA1 and S-OPA1 influences cristae shape and morphology: increased L-OPA1 levels promote cristae stacking and elongated mitochondria, while increased S-OPA1 levels correlated with irregular cristae packing and round mitochondria shape. Coexpression of isoform 1 with shorter alternative products is required for optimal activity in promoting mitochondrial fusion. Isoforms that contain the alternative exon 4b are required for mitochondrial genome maintenance, possibly by anchoring the mitochondrial nucleoids to the inner mitochondrial membrane. Isoforms that contain the alternative exon 4b are required for mitochondrial genome maintenance, possibly by anchoring the mitochondrial nucleoids to the inner mitochondrial membrane.

Subunit / interactions. Oligomeric complex consisting of membrane-bound and soluble forms of OPA1. Interacts with RCC1L; RCC1L acts as a guanine nucleotide exchange factor (GEF) for OPA1 by exchanging bound GDP for free GTP. Interacts with CHCHD3 and IMMT; these interactions occur preferentially with soluble OPA1 forms. Interacts with PRELID1.

Subcellular location. Mitochondrion inner membrane Mitochondrion intermembrane space.

Tissue specificity. Highly expressed in retina. Also expressed in brain, testis, heart and skeletal muscle. Low levels of all isoforms expressed in a variety of tissues. Expressed in retina, skeletal muscle, heart, lung, ovary, colon, thyroid gland, leukocytes and fetal brain. Low levels of all isoforms expressed in a variety of tissues. Isoform 2 expressed in colon, liver, kidney, thyroid gland and leukocytes.

Post-translational modifications. Cleaved by OMA1 or YME1L downstream of the transmembrane region in response to different signals to generate soluble forms. Cleaved by OMA1 at position S1 following stress conditions, generating the short soluble form (Dynamin-like GTPase OPA1, short form; S-OPA1). AFG3L2 is involved in the regulation of OMA1-dependent processing of OPA1. PARL-dependent proteolytic processing releases an antiapoptotic soluble form not required for mitochondrial fusion. Cleavage at position S2 by YME1L is required to mediate oxidative phosphorylation (OXPHOS)-induced mitochondrial fusion. Cleavage occurs in the sequence motif Leu-Gln-Gln-Gln-Ile-Gln (LQQQIQ). Cleavage at position S2 by YME1L is required to mediate oxidative phosphorylation (OXPHOS)-induced mitochondrial fusion. Cleavage occurs in the sequence motif Leu-Gln-Gln-Gln-Ile-Gln (LQQQIQ). Cleavage at position S2 by YME1L is required to mediate oxidative phosphorylation (OXPHOS)-induced mitochondrial fusion. Cleavage occurs in the sequence motif Leu-Gln-Gln-Gln-Ile-Gln (LQQQIQ). Cleavage at position S3 by YME1L is required for membrane tubulation. Cleavage at position S3 by YME1L is required for membrane tubulation.

Disease relevance. Optic atrophy 1 (OPA1) [MIM:165500] A condition that features progressive visual loss in association with optic atrophy. Atrophy of the optic disk indicates a deficiency in the number of nerve fibers which arise in the retina and converge to form the optic disk, optic nerve, optic chiasm and optic tracts. OPA1 is characterized by an insidious onset of visual impairment in early childhood with moderate to severe loss of visual acuity, temporal optic disk pallor, color vision deficits, and centrocecal scotoma of variable density. The disease is caused by variants affecting the gene represented in this entry. Optic atrophy plus syndrome (DOA+) [MIM:125250] An autosomal dominant neurologic disorder characterized most commonly by an insidious onset of visual loss and sensorineural hearing loss in childhood with variable presentation of other clinical manifestations including progressive external ophthalmoplegia, muscle cramps, hyperreflexia, and ataxia. There appears to be a wide range of intermediate phenotypes. The disease is caused by variants affecting the gene represented in this entry. Behr syndrome (BEHRS) [MIM:210000] An autosomal recessive syndrome characterized by optic atrophy beginning in early childhood associated with ataxia, pyramidal signs, spasticity, intellectual disability, and posterior column sensory loss. The ataxia, spasticity, and muscle contractures, mainly of the hip adductors, hamstrings, and soleus, are progressive and become more prominent in the second decade. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial DNA depletion syndrome 14, cardioencephalomyopathic type (MTDPS14) [MIM:616896] An autosomal recessive mitochondrial disorder characterized by lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy. Skeletal muscle biopsies show significant mtDNA depletion and abnormal mitochondria. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by guanine nucleotide exchange factor RCC1L.

Domain organisation. The paddle region plays a major role in driving mitochondrial inner membrane fusion. It binds lipid membranes enriched in negatively charged phospholipids, such as cardiolipin, and promotes membrane tubulation. A conserved intramembrane region, named membrane insertion loop (MIL), within the paddle region inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, driving mitochondrial fusion in cells.

Similarity. Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family.

Isoforms (6)

UniProt ID	Names	Canonical?
O60313-1	1, 6, Sp1	yes
O60313-2	2, 7, Sp7
O60313-9	3, Sp4
O60313-10	4, Sp8
O60313-11	5, Sp5
O60313-13	7, Sp2

RefSeq proteins (10): NP_001341592, NP_001341593, NP_056375, NP_570844, NP_570845, NP_570846, NP_570847, NP_570848, NP_570849, NP_570850* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001401	Dynamin_GTPase	Domain
IPR022812	Dynamin	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR030381	G_DYNAMIN_dom	Domain
IPR045063	Dynamin_N	Domain
IPR045817	OPA1_C	Domain

Pfam: PF00350, PF19434

Enzyme classification (BRENDA):

• EC 3.6.5.5 — dynamin GTPase (BRENDA: 23 organisms, 104 substrates, 250 inhibitors, 42 Km, 26 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	0.0034–2.115	37
ATP	0.2	1

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (199 total): sequence variant 72, mutagenesis site 56, binding site 14, helix 13, strand 11, region of interest 8, site 5, splice variant 4, short sequence motif 3, topological domain 3, chain 2, coiled-coil region 2, transit peptide 1, modified residue 1, disulfide bond 1, transmembrane region 1, intramembrane region 1, domain 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
6JTG	X-RAY DIFFRACTION	2.4
8CT1	ELECTRON MICROSCOPY	4.8
8EEW	ELECTRON MICROSCOPY	5.48
8EFF	ELECTRON MICROSCOPY	5.48
8EFR	ELECTRON MICROSCOPY	5.48
8VLZ	ELECTRON MICROSCOPY	6.4
8VM4	ELECTRON MICROSCOPY	6.4
8CT9	ELECTRON MICROSCOPY	6.8
8EF7	ELECTRON MICROSCOPY	9.68
8EFS	ELECTRON MICROSCOPY	9.68
8EFT	ELECTRON MICROSCOPY	9.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60313-F1	74.02	0.23

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (5): 201–202 (cleavage at site s3); 202–203 (cleavage at site s3); 201–202 (cleavage at site s3); 202–203 (cleavage at site s3); 194–195 (cleavage at site s1)

Ligand- & substrate-binding residues (14): 298; 300; 301; 302; 302; 303; 317; 323; 398; 468; 470; 503 …

Post-translational modifications (1): 228

Disulfide bonds (1): 856–874

Mutagenesis-validated functional residues (56):

Position	Phenotype
213	in interface mutant 9; strongly decreased ability to mediate mitochondrial fusion; when associated with a-217, a-557 and
217	in interface mutant 9; strongly decreased ability to mediate mitochondrial fusion; when associated with a-213, a-557 and
235	in interface mutant 8; strongly decreased ability to mediate mitochondrial fusion.
243	in mutant control 1; does not affect ability to mediate mitochondrial fusion.
248	in mutant control 2; does not affect ability to mediate mitochondrial fusion.
297	abolished gtpase activity without affecting the ability to bind membranes.
298	abolished gtpase activity without affecting the ability to bind membranes.
301	abolished gtpase activity.
302	abolished gtpase activity.
302	abolished gtpase activity without affecting the ability to bind membranes.
316	strongly decreased gtpase activity.
320	decreased gtpase activity.
321	strongly decreased gtpase activity.
322	decreased gtpase activity.
323	abolished gtpase activity.
324	strongly decreased gtpase activity.
359	in mutant control 3; does not affect ability to mediate mitochondrial fusion.
398	strongly decreased gtpase activity.
444	in interface mutant 5; strongly decreased ability to mediate mitochondrial fusion.
503	decreased gtpase activity.
557	in interface mutant 9; strongly decreased ability to mediate mitochondrial fusion; when associated with a-213, a-217 and
565	in interface mutant 9; strongly decreased ability to mediate mitochondrial fusion; when associated with a-213, a-217 and
614–615	in interface mutant 2; strongly decreased ability to mediate mitochondrial fusion; when associated with a-835.
626	in interface mutant 1b; strongly decreased ability to mediate mitochondrial fusion; when associated with a-630, a-668 an
627	in interface mutant 1a; strongly decreased ability to mediate mitochondrial fusion; when associated with a-663 and a-683

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-169911	Regulation of Apoptosis
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 586 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_97, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_AXO_DENDRITIC_TRANSPORT, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_POSITIVE_REGULATION_OF_CELL_FATE_COMMITMENT, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION

GO Biological Process (24): mitochondrial fission (GO:0000266), neural tube closure (GO:0001843), apoptotic process (GO:0006915), mitochondrion organization (GO:0007005), inner mitochondrial membrane organization (GO:0007007), visual perception (GO:0007601), mitochondrial fusion (GO:0008053), peroxisome fission (GO:0016559), axonal transport of mitochondrion (GO:0019896), positive regulation of interleukin-17 production (GO:0032740), cristae formation (GO:0042407), negative regulation of apoptotic process (GO:0043066), GTP metabolic process (GO:0046039), protein complex oligomerization (GO:0051259), negative regulation of release of cytochrome c from mitochondria (GO:0090201), cellular senescence (GO:0090398), membrane tubulation (GO:0097749), negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902236), mitochondrial inner membrane fusion (GO:1990627), positive regulation of T-helper 17 cell lineage commitment (GO:2000330), obsolete mitochondrial genome maintenance (GO:0000002), regulation of mitochondrion organization (GO:0010821), membrane fusion (GO:0061025), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243)

GO Molecular Function (12): magnesium ion binding (GO:0000287), GTPase activity (GO:0003924), GTP binding (GO:0005525), microtubule binding (GO:0008017), phosphatidic acid binding (GO:0070300), GTPase-dependent fusogenic activity (GO:0140523), membrane bending activity (GO:0180020), cardiolipin binding (GO:1901612), nucleotide binding (GO:0000166), protein binding (GO:0005515), lipid binding (GO:0008289), hydrolase activity (GO:0016787)

GO Cellular Component (13): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), cytosol (GO:0005829), microtubule (GO:0005874), membrane (GO:0016020), mitochondrial crista (GO:0030061), dendrite (GO:0030425), mitochondrial membrane (GO:0031966), axon cytoplasm (GO:1904115)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Apoptosis	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
mitochondrion organization	2
organelle fission	2
inner mitochondrial membrane organization	2
binding	2
cytoplasm	2
mitochondrial membrane	2
mitochondrial envelope	2
primary neural tube formation	1
tube closure	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
organelle organization	1
mitochondrial membrane organization	1
sensory perception of light stimulus	1
organelle fusion	1
peroxisome organization	1
mitochondrion transport along microtubule	1
axonal transport	1
axon cytoplasm	1
positive regulation of cytokine production	1
interleukin-17 production	1
regulation of interleukin-17 production	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
purine ribonucleotide metabolic process	1
purine ribonucleoside triphosphate metabolic process	1
protein-containing complex assembly	1
release of cytochrome c from mitochondria	1
negative regulation of organelle organization	1
regulation of release of cytochrome c from mitochondria	1
negative regulation of apoptotic signaling pathway	1
cellular process	1
cellular response to stress	1
membrane organization	1
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1
regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1
negative regulation of response to endoplasmic reticulum stress	1

Protein interactions and networks

STRING

2238 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OPA1	MFN1	Q8IWA4	984
OPA1	MFN2	O95140	908
OPA1	FIS1	Q9Y3D6	903
OPA1	PHB2	Q99623	885
OPA1	PARL	Q9H300	883
OPA1	A0A1W2PP11	A0A1W2PP11	880
OPA1	ATAD1	Q8NBU5	804
OPA1	CYCS	P00001	750
OPA1	MFF	Q9GZY8	736
OPA1	PINK1	Q9BXM7	716
OPA1	OMA1	Q96E52	693
OPA1	MIEF2	Q96C03	685
OPA1	SIRT3	Q9NTG7	661
OPA1	SLC25A46	Q96AG3	657
OPA1	YME1L1	Q96TA2	651

IntAct

116 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GID8	PGRMC2	psi-mi:“MI:0914”(association)	0.640
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
CHCHD4	SSNA1	psi-mi:“MI:0914”(association)	0.640
BNIP3	OPA1	psi-mi:“MI:0915”(physical association)	0.630
OPA1	BNIP3	psi-mi:“MI:0915”(physical association)	0.630
LRRK2	OPA1	psi-mi:“MI:0915”(physical association)	0.600
OPA1	LRRK2	psi-mi:“MI:0915”(physical association)	0.600
OPA1	LRRK2	psi-mi:“MI:0403”(colocalization)	0.600
SCGN	SNAP23	psi-mi:“MI:0914”(association)	0.550
SIRT3	OPA1	psi-mi:“MI:0915”(physical association)	0.540
SIRT3	OPA1	psi-mi:“MI:0407”(direct interaction)	0.540
PRDX3	OPA1	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
SLC30A4	OPA1	psi-mi:“MI:0914”(association)	0.530
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460

BioGRID (276): OPA1 (Affinity Capture-MS), BNIP3 (Affinity Capture-Western), BNIP3 (Two-hybrid), OPA1 (Reconstituted Complex), OPA1 (Affinity Capture-MS), OPA1 (Affinity Capture-MS), OPA1 (Affinity Capture-MS), OPA1 (Affinity Capture-RNA), OPA1 (Co-fractionation), OPA1 (Co-fractionation), OPA1 (Co-fractionation), OPA1 (Affinity Capture-MS), OPA1 (Reconstituted Complex), OPA1 (Affinity Capture-MS), OPA1 (Affinity Capture-MS)

ESM2 similar proteins: B6SJQ0, C6KIE6, C6L7U1, D1FP53, D1FP57, E7BQV0, F4JRS4, F4K2G3, F4K6D3, O22977, O23052, O60313, P56695, Q008S8, Q09263, Q10MI0, Q2QTC2, Q2QWE9, Q2TBM9, Q3EBY6, Q3U213, Q5BPT4, Q5RAM3, Q5RD58, Q5SNQ7, Q620W3, Q697L1, Q6NPP4, Q6ZQ18, Q6ZY51, Q8GSA7, Q8GYY7, Q8L7E9, Q8LFX7, Q8LMR2, Q8S8L9, Q95JR3, Q96JX3, Q9C5Q8, Q9C664

Diamond homologs: A0MWD1, A1E2I4, A1E2I5, A6H7I5, A7VK00, G0SGC7, O00429, O35303, O60313, P09922, P18588, P18589, P18590, P20591, P20592, P20593, P21575, P27594, P27619, P32266, P33237, P33238, P39052, P39053, P39054, P39055, P42697, P50570, P54861, P58281, P79135, P87320, Q000A9, Q05193, Q08877, Q08DF4, Q28379, Q2KIA5, Q2KTC2, Q3UD61

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
STOML2	“up-regulates quantity by expression”	OPA1	“transcriptional regulation”
OPA1	up-regulates	Mitochondrial_fusion
OMA1	“up-regulates activity”	OPA1	cleavage
YME1L1	“up-regulates activity”	OPA1	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 130 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to oxidative stress	7	9.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1753 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	258
Likely pathogenic	93
Uncertain significance	630
Likely benign	494
Benign	89

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012713	NM_130837.3(OPA1):c.820C>T (p.Gln274Ter)	Pathogenic
1012714	NM_130837.3(OPA1):c.2057_2058del (p.His686fs)	Pathogenic
1074910	NM_130837.3(OPA1):c.832del (p.Leu278fs)	Pathogenic
1074919	NM_130837.3(OPA1):c.2197del (p.Gln733fs)	Pathogenic
1074939	NC_000003.12:g.193645729del	Pathogenic
1176167	NM_130837.3(OPA1):c.2284G>T (p.Glu762Ter)	Pathogenic
1176168	NM_130837.3(OPA1):c.2702dup (p.Leu901fs)	Pathogenic
1184499	NM_130837.3(OPA1):c.3G>A (p.Met1Ile)	Pathogenic
1184972	NM_130837.3(OPA1):c.1359del (p.Leu454fs)	Pathogenic
1213866	NM_130837.3(OPA1):c.2293A>T (p.Lys765Ter)	Pathogenic
1297583	NM_130837.3(OPA1):c.1948dup (p.Glu650fs)	Pathogenic
1345404	NM_130837.3(OPA1):c.2661G>A (p.Leu887=)	Pathogenic
1367893	NM_130837.3(OPA1):c.2940del (p.Lys981fs)	Pathogenic
1383594	NM_130837.3(OPA1):c.1581del (p.Glu528fs)	Pathogenic
1394309	NM_130837.3(OPA1):c.3003dup (p.Glu1002fs)	Pathogenic
1400268	NM_130837.3(OPA1):c.1149G>A (p.Lys383=)	Pathogenic
1402595	NM_130837.3(OPA1):c.1214_1215dup (p.Thr406fs)	Pathogenic
1422710	NC_000003.11:g.(?193409832)(193409916_?)del	Pathogenic
1424362	NM_130837.3(OPA1):c.2155C>T (p.Gln719Ter)	Pathogenic
1447573	NM_130837.3(OPA1):c.937A>T (p.Arg313Ter)	Pathogenic
1448649	NM_130837.3(OPA1):c.401G>A (p.Trp134Ter)	Pathogenic
1451185	NM_130837.3(OPA1):c.1408A>G (p.Lys470Glu)	Pathogenic
1451721	NM_130837.3(OPA1):c.2779-2A>T	Pathogenic
1451913	NM_130837.3(OPA1):c.1979_1980del (p.Val660fs)	Pathogenic
1452976	NM_130837.3(OPA1):c.1382_1383del (p.Val461fs)	Pathogenic
1453972	NC_000003.11:g.(?193382649)(193385089_?)del	Pathogenic
1457942	NM_130837.3(OPA1):c.1443dup (p.Gln482fs)	Pathogenic
1458112	NC_000003.11:g.(?193332492)(193409916_?)del	Pathogenic
1458650	NC_000003.11:g.(?193336638)(193344011_?)del	Pathogenic
1459789	NC_000003.11:g.(?193311167)(193311218_?)del	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

6744 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:193615016:T:A	V109D	1.000
3:193637277:C:A	P289Q	1.000
3:193637953:T:A	V291D	1.000
3:193637956:T:A	V292D	1.000
3:193637964:G:A	G295R	1.000
3:193637964:G:C	G295R	1.000
3:193637965:G:A	G295E	1.000
3:193637965:G:T	G295V	1.000
3:193637973:A:C	S298R	1.000
3:193637975:T:A	S298R	1.000
3:193637975:T:G	S298R	1.000
3:193637979:G:A	G300R	1.000
3:193637979:G:C	G300R	1.000
3:193637980:G:A	G300E	1.000
3:193637980:G:T	G300V	1.000
3:193637982:A:C	K301Q	1.000
3:193637986:C:T	T302I	1.000
3:193637988:A:C	S303R	1.000
3:193637990:T:A	S303R	1.000
3:193637990:T:G	S303R	1.000
3:193637998:A:T	E306V	1.000
3:193637999:A:C	E306D	1.000
3:193637999:A:T	E306D	1.000
3:193638007:C:A	A309D	1.000
3:193638019:T:A	I313K	1.000
3:193638061:T:A	V327D	1.000
3:193642772:T:C	L331P	1.000
3:193642796:C:A	A339D	1.000
3:193642829:T:A	L350H	1.000
3:193642985:T:C	L359S	1.000

dbSNP variants (sampled 300 via entrez): RS1000001521 (3:193696089 T>C), RS1000086859 (3:193620077 A>G), RS1000129386 (3:193671125 G>A), RS1000151355 (3:193594012 C>A,G), RS1000176101 (3:193629289 C>T), RS1000213579 (3:193601795 G>A), RS1000248203 (3:193663117 C>T), RS1000337859 (3:193665341 C>T), RS1000339110 (3:193607891 G>A), RS1000346430 (3:193613284 G>T), RS1000354951 (3:193622323 G>C,T), RS1000416351 (3:193616134 C>G,T), RS1000425171 (3:193626355 C>A,T), RS1000432504 (3:193608088 T>C), RS1000471068 (3:193645151 G>A)

Disease associations

OMIM: gene MIM:605290 | disease phenotypes: MIM:165500, MIM:125250, MIM:616896, MIM:210000, MIM:606657, MIM:248200, MIM:120970, MIM:268000, MIM:609129, MIM:621481, MIM:258501, MIM:160150, MIM:166710

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant optic atrophy, classic form	Definitive	Autosomal dominant
optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy	Definitive	Autosomal dominant
optic atrophy	Definitive	Autosomal dominant
mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type)	Strong	Autosomal recessive
Behr syndrome	Strong	Autosomal recessive
OPA1-related optic atrophy with or without extraocular features	Strong	Semidominant
autosomal dominant optic atrophy plus syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR
OPA1-related optic atrophy with or without extraocular features	Definitive	SD

Mondo (25): optic atrophy (MONDO:0003608), autosomal dominant optic atrophy, classic form (MONDO:0008134), inherited retinal dystrophy (MONDO:0019118), optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (MONDO:0007429), mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type) (MONDO:0014820), OPA1-related optic atrophy with or without extraocular features (MONDO:0800181), Behr syndrome (MONDO:0008858), glaucoma, normal tension, susceptibility to (MONDO:0011693), Stargardt disease (MONDO:0019353), ptosis (MONDO:0000728), fatty liver disease (MONDO:0004790), autosomal dominant optic atrophy (MONDO:0020250), cone-rod dystrophy (MONDO:0015993), retinitis pigmentosa (MONDO:0019200), auditory neuropathy (MONDO:0021944)

Orphanet (11): Autosomal dominant optic atrophy, classic form (Orphanet:98673), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Behr syndrome (Orphanet:1239), Stargardt disease (Orphanet:827), Autosomal dominant optic atrophy (Orphanet:98672), Cone rod dystrophy (Orphanet:1872), Retinitis pigmentosa (Orphanet:791), Mitochondrial disease (Orphanet:68380), 3-methylglutaconic aciduria type 3 (Orphanet:67047), Centronuclear myopathy (Orphanet:595), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000556	Retinal dystrophy
HP:0000508	Ptosis

GWAS associations

0 associations (top):

MeSH disease descriptors (16)

Descriptor	Name	Tree numbers
D001763	Blepharoptosis	C11.338.204
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D005234	Fatty Liver	C06.552.241
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D029241	Optic Atrophy, Autosomal Dominant	C10.292.700.225.500.100; C10.574.500.662.100; C11.270.564.100; C11.640.451.451.100; C16.320.290.564.100; C16.320.400.630.100; C18.452.660.665
D009901	Optic Nerve Diseases	C10.292.700; C11.640
D010024	Osteoporosis	C05.116.198.579; C18.452.104.579
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
D000080362	Stargardt Disease	C11.270.872; C11.768.585.439.339; C16.320.290.724
C538268	Auditory neuropathy (supp.)
C537669	Behr syndrome (supp.)
C535311	Costeff optic atrophy syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105705 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 6,222 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1078178	MOMELOTINIB	4	3,481
CHEMBL2103882	TIVANTINIB	3	2,741

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

6 potent at pChembl≥5 of 6 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.77	Kd	17	nM	TIVANTINIB
7.14	Kd	72.92	nM	CHEMBL5653589
7.14	ED50	72.92	nM	CHEMBL5653589
6.55	Kd	280.4	nM	CHEMBL3752910
6.55	ED50	280.4	nM	CHEMBL3752910
6.15	Kd	705	nM	MOMELOTINIB

PubChem BioAssay actives

4 with measured affinity, of 245 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(3R,4R)-3-(1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-3-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione	1425097: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0170	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148914: Binding affinity to human OPA1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0729	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148914: Binding affinity to human OPA1 incubated for 45 mins by Kinobead based pull down assay	kd	0.2804	uM
Momelotinib	1425097: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.7050	uM

CTD chemical–gene interactions

84 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression, increases expression, decreases reaction	3
Acetaminophen	decreases expression	3
Tobacco Smoke Pollution	increases expression, decreases expression	3
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Melatonin	decreases expression, decreases reaction, affects cotreatment, increases expression	2
Rotenone	decreases cleavage, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment, decreases expression	1
sodium arsenate	decreases expression	1
hydroxyhydroquinone	decreases expression	1
dodecyldimethylamine oxide	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases abundance, increases expression	1
salvin	affects reaction, decreases reaction, increases cleavage, increases expression, decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
didecyldimethylammonium	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
justicidins	increases cleavage	1
diafenthiuron	decreases cleavage	1
CGP 52608	affects binding, increases reaction	1
efavirenz	increases expression	1
bardoxolone methyl	increases cleavage	1
lamellarin D	increases cleavage	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991810	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Cellosaurus cell lines

11 cell lines: 9 induced pluripotent stem cell, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1QA	OSRi002-A	Induced pluripotent stem cell
CVCL_A1QB	OSRi003-A	Induced pluripotent stem cell
CVCL_A2VI	GM26117	Transformed cell line	Female
CVCL_A2YJ	BIOi002-A	Induced pluripotent stem cell	Male
CVCL_A4NS	iPS-OPA1-BEHR	Induced pluripotent stem cell	Female
CVCL_B5SF	PUMCHi019-A	Induced pluripotent stem cell	Male
CVCL_C0HC	IBMS-iPSC-074-01	Induced pluripotent stem cell	Female
CVCL_D6BC	HyCyte HEK293 KO-hOPA1	Transformed cell line	Female
CVCL_DQ96	Oex2054SV.4	Induced pluripotent stem cell	Male
CVCL_QX87	IISHDOi003-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

290 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00793988	PHASE4	COMPLETED	Vibration-Assisted Anaesthesia
NCT01239498	PHASE4	UNKNOWN	Saline Injection - Assisted Anesthesia in Eyelid Surgery
NCT02761083	PHASE4	WITHDRAWN	PMCF-study Using Novosyn® Quick Suture Material in Ophthalmic Surgery
NCT04007276	PHASE4	NOT_YET_RECRUITING	The Effect of Lumify™ on Ocular Redness, Intraocular Pressure, and Eyelid Position in Glaucoma Patients
NCT07390578	PHASE4	NOT_YET_RECRUITING	Upneeq vs. Lumify Ptosis
NCT00160407	PHASE4	COMPLETED	Orlistat (Xenical) in the Treatment of Overweight Patients With Nonalcoholic Steatohepatitis (NASH)
NCT00207311	PHASE4	COMPLETED	Study for the Treatment of Significant Steatosis With Xenical Followed by Treatment of Hepatitis C With Pegasys/Copegus
NCT00274495	PHASE4	TERMINATED	Assessing the Efficacy and Safety of Rosiglitazone Added to Standard Therapy for Hepatitis C Genotype 1 With Fatty Liver
NCT00736385	PHASE4	TERMINATED	Metformin for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD)
NCT00742326	PHASE4	TERMINATED	Pioglitazone to Treat Fatty Liver in Patients With HIV and Hepatitis C Infections
NCT01720719	PHASE4	UNKNOWN	Atorvastatin Versus Vitamin E in Treatment of Non-alcoholic Fatty Liver Disease
NCT01761318	PHASE4	COMPLETED	Effect of Liraglutide on Cardiovascular Endpoints in Diabetes Mellitus Type 2 Patients
NCT02102646	PHASE4	COMPLETED	MRI Substudy; Metabolic Changes Due to Iatrogenic Hypogonadism
NCT02210715	PHASE4	COMPLETED	Raltegravir-based Antiretroviral Versus Maintaining Any Other Antiretroviral Therapy in HIV Mono-infected Patients
NCT02660047	PHASE4	COMPLETED	Effect of Liraglutide on Cardiovascular Endpoints in Diabetes Mellitus Type 2 Patients of South Asian Descent
NCT02669641	PHASE4	UNKNOWN	Complex Imaging Assessment of Steatosis
NCT03374358	PHASE4	COMPLETED	Effect on Liver Fat and Metabolic Parameters When Switching a Protease Inhibitor or Efavirenz to Raltegravir
NCT03646292	PHASE4	COMPLETED	Antidiabetic Drugs for Steatotic Liver Disease
NCT03851627	PHASE4	RECRUITING	Effects of Testosterone Undecanoate vs Placebo on Intrahepatic Fat Content in Overweight/Obese Men With T2DM or Prediabetes and Hypogonadism
NCT05898841	PHASE4	COMPLETED	Study to Evaluate the Efficacy and Safety of a Rilpivarine-based Antiretroviral Tratment Regimen in HIV- Infected Patients With Liver Metabolic Disease Who Maintain Udetectable HIV Viral Load
NCT06989723	PHASE4	RECRUITING	Pioglitazone and Empagliflozin for Fatty Liver Disease in Type 2 Diabetes
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT03772665	PHASE3	COMPLETED	Safety and Efficacy of Emixustat in Stargardt Disease
NCT05244304	PHASE3	COMPLETED	Phase 3, Randomized, Placebo-Controlled Study of Tinlarebant to Explore Safety and Efficacy in Adolescent Stargardt Disease
NCT07419334	PHASE3	RECRUITING	Study of ALK-001 on the Progression of Stargardt Disease
NCT02436759	PHASE3	COMPLETED	Study of the Safety and Efficacy of RVL-1201 in the Treatment of Acquired Blepharoptosis
NCT03536949	PHASE3	COMPLETED	Study of Safety of RVL-1201 in Treatment of Blepharoptosis
NCT03565887	PHASE3	COMPLETED	Study of Safety and Efficacy of RVL-1201 in the Treatment of Blepharoptosis
NCT05945615	PHASE3	COMPLETED	Oxymetazoline Drops for Acquired Blepharoptosis From Synkinesis
NCT06683651	PHASE3	RECRUITING	A Study in Chinese Patients With Acquired Blepharoptosis
NCT00063635	PHASE3	COMPLETED	Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC)
NCT00244569	PHASE3	COMPLETED	Development of a Breath Test for Monitoring Patients With Liver Disease
NCT00576667	PHASE3	TERMINATED	An Efficacy and Safety Study of Rimonabant for Treatment of Nonalcoholic Steatohepatitis (NASH) in Patients Without Diabetes
NCT00577148	PHASE3	TERMINATED	An Efficacy and Safety Study of Rimonabant for Treatment of Nonalcoholic Steatohepatitis (NASH) in Patients With Type 2 Diabetes
NCT01934777	PHASE3	COMPLETED	Efficacy and Tolerance of Treatment With DHA, Choline and Vitamin E in Children With Non-alcoholic Steatohepatitis
NCT01992809	PHASE3	COMPLETED	Omega 3 Supplementation in Fatty Liver
NCT02265276	PHASE3	UNKNOWN	A Prospective, Randomized Trial to Compare saroGLitazar With pioglitAZone in Nonalcoholic Fatty livEr Disease
NCT05308160	PHASE3	UNKNOWN	A Single Center, Randomized, Open Label, Parallel Group, Phase 3 Study to Evaluate the Efficacy of Dapagliflozin in Subjects With Nonalcoholic Fatty Liver Disease
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy