Leber hereditary optic neuropathy
diseaseOn this page
Also known as Leber Hereditary optic atrophyLeber optic atrophyLeber’s diseaseLHONoptic atrophy, Leber type
Summary
Leber hereditary optic neuropathy (MONDO:0010788) is a disease caused by variants in MT-ND1, MT-ND4, MT-ND5, and 1 other genes, with 18 cohort genes and 21 clinical trials. The dominant Reactome pathway is Mitochondrial translation termination (11 cohort genes). Top therapeutic interventions include cyclosporine, niacinamide, and sonlicromanol.
At a glance
- Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
- Causal genes: MT-ND1 (GenCC Definitive), MT-ND4 (GenCC Definitive), MT-ND5 (GenCC Strong), MT-ND6 (GenCC Strong)
- Cohort genes: 18
- ClinVar variants: 84
- Phenotypes (HPO): 20
- Clinical trials: 21
Clinical features
Epidemiology
Prevalence records
7 prevalence record(s), Orphanet:
| Type | Class | Value | Geography | Validation |
|---|---|---|---|---|
| Point prevalence | 1-9 / 100 000 | 4.3 | Worldwide | Validated |
| Point prevalence | 1-9 / 100 000 | 2.3 | Europe | Validated |
| Point prevalence | 1-9 / 100 000 | 2.6 | Netherlands | Validated |
| Point prevalence | 1-9 / 100 000 | 2 | Finland | Validated |
| Point prevalence | 1-9 / 100 000 | 1.85 | Denmark | Validated |
| Point prevalence | 1-9 / 100 000 | 1.9743 | Japan | Validated |
| Point prevalence | 1-9 / 100 000 | 3.22 | United Kingdom | Not yet validated |
Signs & symptoms
Clinical features (HPO)
20 HPO clinical features (Orphanet curated; top 20 by frequency):
| HPO ID | Term | Frequency |
|---|---|---|
| HP:0007924 | Slow decrease in visual acuity | Very frequent (80-99%) |
| HP:0200125 | Mitochondrial respiratory chain defects | Very frequent (80-99%) |
| HP:0000529 | Progressive visual loss | Frequent (30-79%) |
| HP:0000576 | Centrocecal scotoma | Frequent (30-79%) |
| HP:0000603 | Central scotoma | Frequent (30-79%) |
| HP:0000622 | Blurred vision | Frequent (30-79%) |
| HP:0000648 | Optic atrophy | Frequent (30-79%) |
| HP:0007763 | Retinal telangiectasia | Frequent (30-79%) |
| HP:0012841 | Retinal vascular tortuosity | Frequent (30-79%) |
| HP:0000512 | Abnormal electroretinogram | Occasional (5-29%) |
| HP:0000551 | Color vision defect | Occasional (5-29%) |
| HP:0000649 | Abnormality of visual evoked potentials | Occasional (5-29%) |
| HP:0001251 | Ataxia | Occasional (5-29%) |
| HP:0002174 | Postural tremor | Occasional (5-29%) |
| HP:0003198 | Myopathy | Occasional (5-29%) |
| HP:0004309 | Ventricular preexcitation | Occasional (5-29%) |
| HP:0009830 | Peripheral neuropathy | Occasional (5-29%) |
| HP:0011675 | Arrhythmia | Occasional (5-29%) |
| HP:0020120 | Retinal nerve fiber edema | Occasional (5-29%) |
| HP:0032036 | Reduced contrast sensitivity | Occasional (5-29%) |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | Leber hereditary optic neuropathy |
| Mondo ID | MONDO:0010788 |
| MeSH | D029242 |
| OMIM | 535000 |
| Orphanet | 104 |
| DOID | DOID:705 |
| ICD-11 | 1018428959 |
| NCIT | C84808 |
| SNOMED CT | 58610003 |
| UMLS | C0917796 |
| MedGen | 182973 |
| GARD | 0006870 |
| NORD | 1352 |
| Is cancer (heuristic) | no |
Also known as: Leber Hereditary optic atrophy · Leber hereditary optic neuropathy · Leber optic atrophy · Leber’s disease · LHON · optic atrophy, Leber type
Data availability: 84 ClinVar variants · 16 GenCC gene-disease records · 17 cell lines.
Disease family
An umbrella term covering 1 Mondo subtype.
Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › dilated cardiomyopathy › familial dilated cardiomyopathy › Leber hereditary optic neuropathy
Related subtypes (28): autosomal recessive limb-girdle muscular dystrophy type 2C, Barth syndrome, histiocytoid cardiomyopathy, Kearns-Sayre syndrome, autosomal recessive limb-girdle muscular dystrophy type 2F, myofibrillar myopathy 1, autosomal recessive limb-girdle muscular dystrophy type 2E, dilated cardiomyopathy 1J, hypertrophic cardiomyopathy 25, autosomal recessive limb-girdle muscular dystrophy type 2D, DK1-congenital disorder of glycosylation, autosomal recessive limb-girdle muscular dystrophy type 2M, early-onset myopathy with fatal cardiomyopathy, PGM1-congenital disorder of glycosylation, autosomal recessive limb-girdle muscular dystrophy type 2W, symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers, Emery-Dreifuss muscular dystrophy, familial isolated dilated cardiomyopathy, cardiomyopathy, dilated, 1LL, cardiomyopathy, dilated, 1MM, cardiomyopathy, dilated, 100, cardiomyopathy, dilated, 2I, cardiomyopathy, dilated, 2j, cardiomyopathy, dilated, 2K, cardiomyopathy, dilated, 2l, cardiomyopathy, dilated, 1QQ, cardiomyopathy, dilated, 2M, cardiomyopathy, dilated, 3C
Subtypes (1): Leber optic atrophy and dystonia
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
84 retrieved; paginated sample, class counts are floors:
28 uncertain significance, 19 likely pathogenic, 18 benign, 10 pathogenic, 5 benign/likely benign, 2 likely benign, 1 not provided, 1 risk factor
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 9641 | NC_012920.1(MT-ATP6):m.8993T>G | MT-ATP6 | Pathogenic | reviewed by expert panel |
| 9642 | NC_012920.1(MT-ATP6):m.8993T>C | MT-ATP6 | Pathogenic | reviewed by expert panel |
| 9644 | NC_012920.1(MT-ATP6):m.9176T>C | MT-ATP6 | Pathogenic | reviewed by expert panel |
| 9647 | NC_012920.1(MT-ATP6):m.9185T>C | MT-ATP6 | Pathogenic | reviewed by expert panel |
| 9722 | NC_012920.1(MT-ND1):m.3460G>A | MT-ND1 | Pathogenic | reviewed by expert panel |
| 9708 | NC_012920.1(MT-ND4):m.11778G>A | MT-ND4 | Pathogenic | reviewed by expert panel |
| 693516 | NC_012920.1(MT-ND5):m.13094T>C | MT-ND5 | Pathogenic | reviewed by expert panel |
| 9689 | NC_012920.1(MT-ND6):m.14459G>A | MT-ND5 | Pathogenic | reviewed by expert panel |
| 9688 | NC_012920.1(MT-ND6):m.14484T>C | MT-ND6 | Pathogenic | reviewed by expert panel |
| 9694 | NC_012920.1(MT-ND6):m.14487T>C | MT-ND6 | Pathogenic | reviewed by expert panel |
| 191364 | NC_012920.1(MT-ATP6):m.8969G>A | MT-ATP6 | Likely pathogenic | reviewed by expert panel |
| 690280 | NC_012920.1(MT-ATP6):m.9035T>C | MT-ATP6 | Likely pathogenic | reviewed by expert panel |
| 9646 | NC_012920.1(MT-CO3):m.9205_9206del | MT-ATP6 | Likely pathogenic | reviewed by expert panel |
| 9650 | NC_012920.1(MT-ATP6):m.9176T>G | MT-ATP6 | Likely pathogenic | reviewed by expert panel |
| 9681 | NC_012920.1(MT-CYB):m.15150G>A | MT-CYB | Likely pathogenic | reviewed by expert panel |
| 65518 | NC_012920.1(MT-ND1):m.3635G>A | MT-ND1 | Likely pathogenic | reviewed by expert panel |
| 9733 | NC_012920.1(MT-ND1):m.3697G>A | MT-ND1 | Likely pathogenic | reviewed by expert panel |
| 9711 | NC_012920.1(MT-ND4):m.11777C>A | MT-ND4 | Likely pathogenic | reviewed by expert panel |
| 9707 | NC_012920.1(MT-ND4L):m.10663T>C | MT-ND4L | Likely pathogenic | reviewed by expert panel |
| 2443068 | NC_012920.1(MT-ND5):m.12923G>A | MT-ND5 | Likely pathogenic | criteria provided, single submitter |
| 693440 | NC_012920.1(MT-ND5):m.12425del | MT-ND5 | Likely pathogenic | reviewed by expert panel |
| 9698 | NC_012920.1(MT-ND5):m.12706T>C (p.Phe124Leu) | MT-ND5 | Likely pathogenic | reviewed by expert panel |
| 9703 | NC_012920.1(MT-ND5):m.13042G>A | MT-ND5 | Likely pathogenic | reviewed by expert panel |
| 65513 | NC_012920.1(MT-ND6):m.14482C>G | MT-ND6 | Likely pathogenic | reviewed by expert panel |
| 65515 | NC_012920.1(MT-ND6):m.14568C>T | MT-ND6 | Likely pathogenic | reviewed by expert panel |
| 9691 | NC_012920.1(MT-ND6):m.14495A>G | MT-ND6 | Likely pathogenic | reviewed by expert panel |
| 9693 | NC_012920.1(MT-ND6):m.14482C>A | MT-ND6 | Likely pathogenic | reviewed by expert panel |
| 9734 | NC_012920.1(MT-ND1):m.3946G>A | MT-TF | Likely pathogenic | reviewed by expert panel |
| 522715 | NM_001377299.1(NDUFS2):c.268G>A (p.Ala90Thr) | NDUFS2 | Likely pathogenic | criteria provided, single submitter |
| 992950 | NM_006150.5(PRICKLE3):c.157C>T (p.Arg53Trp) | PRICKLE3 | risk factor | no assertion criteria provided |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 51 · Orphanet: 58 · 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 |
|---|---|---|---|---|
| MT-ND1 | Definitive | Mitochondrial | Leber hereditary optic neuropathy | 5 |
| MT-ND4 | Definitive | Mitochondrial | Leber hereditary optic neuropathy | 5 |
| DNAJC30 | Strong | Autosomal recessive | Leber hereditary optic neuropathy, autosomal recessive | 4 |
| MT-ND5 | Strong | Mitochondrial | Leber hereditary optic neuropathy | 5 |
| MT-ND6 | Strong | Mitochondrial | Leber hereditary optic neuropathy | 5 |
| MT-ATP6 | Supportive | Mitochondrial | Leber hereditary optic neuropathy | 8 |
| MT-CO3 | Supportive | Mitochondrial | Leber hereditary optic neuropathy | 3 |
| MT-CYB | Supportive | Mitochondrial | Leber hereditary optic neuropathy | 2 |
| MT-ND2 | Supportive | Mitochondrial | Leber hereditary optic neuropathy | 3 |
| MT-ND4L | Supportive | Mitochondrial | Leber hereditary optic neuropathy | |
| NDUFS2 | Supportive | Mitochondrial | Leber hereditary optic neuropathy | 9 |
| PRICKLE3 | Limited | X-linked | Leber hereditary optic neuropathy |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| MT-ATP6 | Orphanet:104 | Leber hereditary optic neuropathy |
| MT-ATP6 | Orphanet:225154 | Familial infantile bilateral striatal necrosis |
| MT-ATP6 | Orphanet:254913 | Isolated ATP synthase deficiency |
| MT-ATP6 | Orphanet:255210 | Mitochondrial DNA-associated Leigh syndrome |
| MT-ATP6 | Orphanet:320360 | MT-ATP6-related mitochondrial spastic paraplegia |
| MT-ATP6 | Orphanet:397750 | Periodic paralysis with later-onset distal motor neuropathy |
| MT-ATP6 | Orphanet:644 | NARP syndrome |
| MT-CO3 | Orphanet:104 | Leber hereditary optic neuropathy |
| MT-CO3 | Orphanet:254905 | Isolated cytochrome C oxidase deficiency |
| MT-CO3 | Orphanet:550 | MELAS |
| MT-CO3 | Orphanet:99845 | Genetic recurrent myoglobinuria |
| MT-CYB | Orphanet:104 | Leber hereditary optic neuropathy |
| MT-CYB | Orphanet:137675 | Histiocytoid cardiomyopathy |
| MT-CYB | Orphanet:1460 | Isolated complex III deficiency |
| MT-ND1 | Orphanet:104 | Leber hereditary optic neuropathy |
| MT-ND1 | Orphanet:255210 | Mitochondrial DNA-associated Leigh syndrome |
| MT-ND1 | Orphanet:2609 | Isolated complex I deficiency |
| MT-ND1 | Orphanet:550 | MELAS |
| MT-ND2 | Orphanet:104 | Leber hereditary optic neuropathy |
| MT-ND2 | Orphanet:255210 | Mitochondrial DNA-associated Leigh syndrome |
| MT-ND2 | Orphanet:2609 | Isolated complex I deficiency |
| MT-ND4 | Orphanet:104 | Leber hereditary optic neuropathy |
| MT-ND4 | Orphanet:255210 | Mitochondrial DNA-associated Leigh syndrome |
| MT-ND4 | Orphanet:550 | MELAS |
| MT-ND4 | Orphanet:90641 | Rare mitochondrial non-syndromic sensorineural deafness |
| MT-ND4 | Orphanet:99718 | Leber plus disease |
| MT-ND4L | Orphanet:104 | Leber hereditary optic neuropathy |
| MT-ND5 | Orphanet:104 | Leber hereditary optic neuropathy |
| MT-ND5 | Orphanet:255210 | Mitochondrial DNA-associated Leigh syndrome |
| MT-ND5 | Orphanet:550 | MELAS |
| MT-ND5 | Orphanet:551 | MERRF |
| MT-ND6 | Orphanet:104 | Leber hereditary optic neuropathy |
| MT-ND6 | Orphanet:255210 | Mitochondrial DNA-associated Leigh syndrome |
| MT-ND6 | Orphanet:550 | MELAS |
| MT-ND6 | Orphanet:99718 | Leber plus disease |
| NDUFS2 | Orphanet:104 | Leber hereditary optic neuropathy |
| NDUFS2 | Orphanet:2609 | Isolated complex I deficiency |
| DNAJC30 | Orphanet:104 | Leber hereditary optic neuropathy |
| DNAJC30 | Orphanet:904 | Williams syndrome |
| RP1 | Orphanet:791 | Retinitis pigmentosa |
| MAPRE2 | Orphanet:2505 | Multiple benign circumferential skin creases on limbs |
| MT-CO1 | Orphanet:104 | Leber hereditary optic neuropathy |
| MT-CO1 | Orphanet:254905 | Isolated cytochrome C oxidase deficiency |
| MT-CO1 | Orphanet:550 | MELAS |
| MT-CO1 | Orphanet:90641 | Rare mitochondrial non-syndromic sensorineural deafness |
| MT-CO1 | Orphanet:99845 | Genetic recurrent myoglobinuria |
| MT-ND3 | Orphanet:255210 | Mitochondrial DNA-associated Leigh syndrome |
| MT-ND3 | Orphanet:2609 | Isolated complex I deficiency |
| MT-ND3 | Orphanet:99718 | Leber plus disease |
| MT-TF | Orphanet:550 | MELAS |
Cohort genes → proteins
18 cohort genes, 16 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 18 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| PRICKLE3 | HGNC:6645 | ENSG00000012211 | O43900 | Prickle planar cell polarity protein 3 | gencc,clinvar |
| MT-ATP6 | HGNC:7414 | ENSG00000198899 | P00846 | ATP synthase F(0) complex subunit a | gencc,clinvar |
| MT-CO3 | HGNC:7422 | ENSG00000198938 | P00414 | Cytochrome c oxidase subunit 3 | gencc,clinvar |
| MT-CYB | HGNC:7427 | ENSG00000198727 | P00156 | Cytochrome b | gencc,clinvar |
| MT-ND1 | HGNC:7455 | ENSG00000198888 | P03886 | NADH-ubiquinone oxidoreductase chain 1 | gencc,clinvar |
| MT-ND2 | HGNC:7456 | ENSG00000198763 | P03891 | NADH-ubiquinone oxidoreductase chain 2 | gencc,clinvar |
| MT-ND4 | HGNC:7459 | ENSG00000198886 | C0HME5 | Mitochondrial alternative ND4 protein | gencc,clinvar |
| MT-ND4L | HGNC:7460 | ENSG00000212907 | P03901 | NADH-ubiquinone oxidoreductase chain 4L | gencc,clinvar |
| MT-ND5 | HGNC:7461 | ENSG00000198786 | P03915 | NADH-ubiquinone oxidoreductase chain 5 | gencc,clinvar |
| MT-ND6 | HGNC:7462 | ENSG00000198695 | P03923 | NADH-ubiquinone oxidoreductase chain 6 | gencc,clinvar |
| NDUFS2 | HGNC:7708 | ENSG00000158864 | O75306 | NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial | gencc,clinvar |
| DNAJC30 | HGNC:16410 | ENSG00000176410 | Q96LL9 | DnaJ homolog subfamily C member 30, mitochondrial | gencc |
| RP1 | HGNC:10263 | ENSG00000104237 | P56715 | Oxygen-regulated protein 1 | clinvar |
| MAPRE2 | HGNC:6891 | ENSG00000166974 | Q15555 | Microtubule-associated protein RP/EB family member 2 | clinvar |
| MT-CO1 | HGNC:7419 | ENSG00000198804 | P00395 | Cytochrome c oxidase subunit 1 | clinvar |
| MT-ND3 | HGNC:7458 | ENSG00000198840 | P03897 | NADH-ubiquinone oxidoreductase chain 3 | clinvar |
| MT-TF | HGNC:7481 | ENSG00000210049 | mitochondrially encoded tRNA-Phe (UUU/C) | clinvar | |
| MT-TL1 | HGNC:7490 | ENSG00000209082 | mitochondrially encoded tRNA-Leu (UUA/G) 1 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| PRICKLE3 | Prickle planar cell polarity protein 3 | Involved in the planar cell polarity (PCP) pathway that is essential for the polarization of epithelial cells during morphogenetic processes, including gastrulation and neurulation. |
| MT-ATP6 | ATP synthase F(0) complex subunit a | Subunit a, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of th… |
| MT-CO3 | Cytochrome c oxidase subunit 3 | Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. |
| MT-CYB | Cytochrome b | Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain. |
| MT-ND1 | NADH-ubiquinone oxidoreductase chain 1 | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. |
| MT-ND2 | NADH-ubiquinone oxidoreductase chain 2 | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. |
| MT-ND4 | Mitochondrial alternative ND4 protein | Regulates mitochondrial respiration by decreasing oxygen consumption. |
| MT-ND4L | NADH-ubiquinone oxidoreductase chain 4L | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. |
| MT-ND5 | NADH-ubiquinone oxidoreductase chain 5 | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. |
| MT-ND6 | NADH-ubiquinone oxidoreductase chain 6 | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. |
| NDUFS2 | NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. |
| DNAJC30 | DnaJ homolog subfamily C member 30, mitochondrial | Mitochondrial protein enriched in neurons that acts as a regulator of mitochondrial respiration. |
| RP1 | Oxygen-regulated protein 1 | Microtubule-associated protein regulating the stability and length of the microtubule-based axoneme of photoreceptors. |
| MAPRE2 | Microtubule-associated protein RP/EB family member 2 | Adapter protein that is involved in microtubule polymerization, and spindle function by stabilizing microtubules and anchoring them at centrosomes. |
| MT-CO1 | Cytochrome c oxidase subunit 1 | Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. |
| MT-ND3 | NADH-ubiquinone oxidoreductase chain 3 | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor. |
Protein-family classification
Druggable: 1 · Difficult: 1 · Unknown: 16 · Druggable fraction: 0.06
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 |
|---|---|---|---|
| Other/Unknown | 16 | 1.6× | 0.009 |
| Enzyme (other) | 1 | 0.7× | 0.902 |
| Transcription factor | 1 | 0.5× | 0.902 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| PRICKLE3 | Transcription factor | no | Znf_LIM, PET_domain, PET_prickle | |
| MT-ATP6 | Other/Unknown | no | ATP_synth_F0_asu, ATP_synth_F0_asu_AS, F0_ATP_A_sf | |
| MT-CO3 | Other/Unknown | no | Cyt_c_oxidase-like_su3, Cyt_c_oxidase_su3_a-hlx, Cyt_c/ubiquinol_Oxase_su3 | |
| MT-CYB | Other/Unknown | no | Cyt_b/b6_N, Cyt_b/b6_C, Di-haem_cyt_TM | |
| MT-ND1 | Other/Unknown | no | NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS | |
| MT-ND2 | Other/Unknown | no | ND/Mrp_TM, NADH_UbQ_OxRdtase_chain2, NADH_DH_su2_C | |
| MT-ND4 | Other/Unknown | no | NADH4_N, ND/Mrp_TM, NADH_UbQ_OxRdtase | |
| MT-ND4L | Other/Unknown | no | NADH_UbQ_OxRdtase_chain4L/K, NUOK/Mnh_C1-like | |
| MT-ND5 | Other/Unknown | no | Proton_antipo_N, ND/Mrp_TM, NU5C-like | |
| MT-ND6 | Other/Unknown | no | NADH_UbQ/plastoQ_OxRdtase_su6, ComplexI_Subunit6 | |
| NDUFS2 | Other/Unknown | no | NADH_Q_OxRdtase_suD, NADH_UbQ_OxRdtase_49kDa_CS, NDH1_su_D/H | |
| DNAJC30 | Other/Unknown | no | DnaJ_domain, J_dom_sf, Mito_ATP_Synthase-Asso | |
| RP1 | Other/Unknown | no | Doublecortin_dom, Doublecortin_dom_sf | |
| MAPRE2 | Other/Unknown | no | CH_dom, EB1_C, MAPRE | |
| MT-CO1 | Enzyme (other) | yes | 7.1.1.9 | Cyt_C_Oxase_1, Cyt_c_Oxase_su1_BS, Cyt_c_oxase-like_su1_dom |
| MT-ND3 | Other/Unknown | no | NADH_UbQ/plastoQ_OxRdtase_su3, NDAH_ubi_oxred_su3_sf | |
| MT-TF | Other/Unknown | no | ||
| MT-TL1 | Other/Unknown | no |
Expression context
Cohort genes with no expression data: 0.
18 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) | 18 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| apex of heart | 4 |
| right uterine tube | 4 |
| gastrocnemius | 3 |
| left uterine tube | 3 |
| rectum | 3 |
| zone of skin | 3 |
| adipose tissue | 3 |
| mucosa of stomach | 2 |
| frontal cortex | 2 |
| granulocyte | 2 |
| lower esophagus mucosa | 1 |
| muscle of leg | 1 |
| descending thoracic aorta | 1 |
| endocervix | 1 |
| pituitary gland | 1 |
| cortex of kidney | 1 |
| heart right ventricle | 1 |
| lateral nuclear group of thalamus | 1 |
| postcentral gyrus | 1 |
| heart left ventricle | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| PRICKLE3 | 169 | ubiquitous | marker | lower esophagus mucosa, gastrocnemius, muscle of leg |
| MT-ATP6 | 134 | ubiquitous | marker | mucosa of stomach, left uterine tube, descending thoracic aorta |
| MT-CO3 | 134 | ubiquitous | marker | zone of skin, endocervix, rectum |
| MT-CYB | 134 | ubiquitous | marker | apex of heart, pituitary gland, zone of skin |
| MT-ND1 | 134 | ubiquitous | marker | adipose tissue, gastrocnemius, frontal cortex |
| MT-ND2 | 134 | broad | marker | adipose tissue, right uterine tube, left uterine tube |
| MT-ND4 | 134 | ubiquitous | marker | right uterine tube, apex of heart, zone of skin |
| MT-ND4L | 134 | ubiquitous | marker | rectum, cortex of kidney, apex of heart |
| MT-ND5 | 247 | ubiquitous | marker | heart right ventricle, postcentral gyrus, lateral nuclear group of thalamus |
| MT-ND6 | 134 | ubiquitous | marker | mucosa of stomach, left uterine tube, right uterine tube |
| NDUFS2 | 292 | ubiquitous | marker | apex of heart, gastrocnemius, heart left ventricle |
| DNAJC30 | 255 | ubiquitous | marker | tibialis anterior, pancreatic ductal cell, kidney epithelium |
| RP1 | 103 | tissue_specific | marker | right uterine tube, olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis |
| MAPRE2 | 300 | ubiquitous | marker | cortical plate, dorsal root ganglion, corpus callosum |
| MT-CO1 | 134 | ubiquitous | marker | granulocyte, stromal cell of endometrium, rectum |
| MT-ND3 | 134 | ubiquitous | marker | granulocyte, adipose tissue, left lobe of thyroid gland |
| MT-TF | 118 | ubiquitous | marker | prefrontal cortex, amygdala, skeletal muscle tissue |
| MT-TL1 | 118 | ubiquitous | marker | frontal cortex, right frontal lobe, caudate nucleus |
Protein interactions among cohort
Intra-cohort edges: 49.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| NDUFS2 | 4,412 |
| MT-CO1 | 3,547 |
| MT-ND1 | 3,537 |
| MT-CYB | 3,317 |
| MT-ND3 | 2,923 |
| MT-ATP6 | 2,869 |
| MT-ND5 | 2,825 |
| MT-ND2 | 2,658 |
| MAPRE2 | 2,195 |
| MT-CO3 | 1,791 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| DNAJC30 | MT-ATP6 | intact, string_interaction |
| DNAJC30 | MT-ND1 | intact |
| MT-ATP6 | MT-CO1 | string_interaction |
| MT-ATP6 | MT-CO3 | string_interaction |
| MT-ATP6 | MT-CYB | string_interaction |
| MT-ATP6 | MT-ND1 | string_interaction |
| MT-ATP6 | MT-ND2 | string_interaction |
| MT-ATP6 | MT-ND3 | string_interaction |
| MT-ATP6 | MT-ND4L | string_interaction |
| MT-ATP6 | MT-ND5 | string_interaction |
| MT-ATP6 | MT-ND6 | string_interaction |
| MT-CO1 | MT-CO3 | string_interaction |
| MT-CO1 | MT-CYB | string_interaction |
| MT-CO1 | MT-ND1 | string_interaction |
| MT-CO1 | MT-ND2 | string_interaction |
| MT-CO1 | MT-ND3 | string_interaction |
| MT-CO1 | MT-ND4L | string_interaction |
| MT-CO1 | MT-ND5 | string_interaction |
| MT-CO1 | MT-ND6 | string_interaction |
| MT-CO3 | MT-CYB | string_interaction |
| MT-CO3 | MT-ND1 | string_interaction |
| MT-CO3 | MT-ND2 | string_interaction |
| MT-CO3 | MT-ND3 | string_interaction |
| MT-CO3 | MT-ND4L | string_interaction |
| MT-CO3 | MT-ND5 | string_interaction |
| MT-CO3 | MT-ND6 | string_interaction |
| MT-CYB | MT-ND1 | string_interaction |
| MT-CYB | MT-ND2 | string_interaction |
| MT-CYB | MT-ND3 | string_interaction |
| MT-CYB | MT-ND4L | string_interaction |
| MT-CYB | MT-ND5 | string_interaction |
| MT-CYB | MT-ND6 | string_interaction |
| MT-ND1 | MT-ND2 | string_interaction |
| MT-ND1 | MT-ND3 | string_interaction |
| MT-ND1 | MT-ND4L | string_interaction |
| MT-ND1 | MT-ND5 | string_interaction |
| MT-ND1 | MT-ND6 | string_interaction |
| MT-ND1 | NDUFS2 | string_interaction |
| MT-ND2 | MT-ND3 | string_interaction |
| MT-ND2 | MT-ND4L | string_interaction |
| MT-ND2 | MT-ND5 | string_interaction |
| MT-ND2 | MT-ND6 | string_interaction |
| MT-ND3 | MT-ND4L | string_interaction |
| MT-ND3 | MT-ND5 | string_interaction |
| MT-ND3 | MT-ND6 | string_interaction |
| MT-ND4L | MT-ND5 | string_interaction |
| MT-ND4L | MT-ND6 | string_interaction |
| MT-ND5 | MT-ND6 | string_interaction |
| MT-ND6 | NDUFS2 | biogrid_interaction |
Structural data
PDB: 13 · AlphaFold-only: 3 · No structure: 2
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| MT-ATP6 | P00846 | 10 |
| NDUFS2 | O75306 | 8 |
| MT-ND2 | P03891 | 7 |
| MT-ND4 | C0HME5 | 7 |
| MT-ND5 | P03915 | 7 |
| MT-CYB | P00156 | 5 |
| MT-ND1 | P03886 | 5 |
| MT-ND4L | P03901 | 5 |
| MT-ND6 | P03923 | 5 |
| MT-ND3 | P03897 | 5 |
| MT-CO3 | P00414 | 3 |
| MT-CO1 | P00395 | 3 |
| DNAJC30 | Q96LL9 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| MAPRE2 | Q15555 | 75.12 |
| PRICKLE3 | O43900 | 67.96 |
| RP1 | P56715 | 37.45 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 18 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Mitochondrial translation termination | 11 | 100.7× | 4e-21 | MT-ATP6, MT-CO3, MT-CYB, MT-ND1, MT-ND2, MT-ND4, MT-ND4L, MT-ND5 (+3 more) |
| Respiratory electron transport | 10 | 79.3× | 5e-18 | MT-CO3, MT-CYB, MT-ND1, MT-ND2, MT-ND4, MT-ND5, MT-ND6, NDUFS2 (+2 more) |
| Complex I biogenesis | 7 | 96.5× | 8e-13 | MT-ND1, MT-ND2, MT-ND4, MT-ND5, MT-ND6, NDUFS2, MT-ND3 |
| Mitochondrial protein degradation | 6 | 57.1× | 1e-09 | MT-ATP6, MT-ND1, MT-ND2, MT-ND5, MT-ND6, MT-CO1 |
| Complex IV assembly | 2 | 38.1× | 0.004 | MT-CO3, MT-CO1 |
| Cytoprotection by HMOX1 | 2 | 30.7× | 0.005 | MT-CO3, MT-CO1 |
| TP53 Regulates Metabolic Genes | 2 | 21.6× | 0.008 | MT-CO3, MT-CO1 |
| Aerobic respiration and respiratory electron transport | 2 | 14.8× | 0.015 | MT-ATP6, NDUFS2 |
| Formation of ATP by chemiosmotic coupling | 1 | 47.6× | 0.035 | MT-ATP6 |
| Complex III assembly | 1 | 36.6× | 0.040 | MT-CYB |
| Cristae formation | 1 | 28.8× | 0.047 | MT-ATP6 |
| Mitochondrial biogenesis | 1 | 14.0× | 0.086 | MT-ATP6 |
| Organelle biogenesis and maintenance | 1 | 5.5× | 0.193 | MT-ATP6 |
| Metabolism | 2 | 1.9× | 0.296 | MT-ATP6, NDUFS2 |
| Metabolism of proteins | 1 | 1.0× | 0.636 | MT-ATP6 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| proton motive force-driven mitochondrial ATP synthesis | 9 | 148.1× | 6e-17 | MT-ATP6, MT-ND1, MT-ND2, MT-ND4, MT-ND4L, MT-ND5, MT-ND6, NDUFS2 (+1 more) |
| aerobic respiration | 9 | 139.4× | 6e-17 | MT-ND1, MT-ND2, MT-ND4, MT-ND4L, MT-ND5, MT-ND6, NDUFS2, MT-CO1 (+1 more) |
| mitochondrial electron transport, NADH to ubiquinone | 8 | 179.3× | 5e-16 | MT-ND1, MT-ND2, MT-ND4, MT-ND4L, MT-ND5, MT-ND6, NDUFS2, MT-ND3 |
| mitochondrial respiratory chain complex I assembly | 6 | 154.1× | 2e-11 | MT-ND1, MT-ND2, MT-ND4, MT-ND5, MT-ND6, NDUFS2 |
| electron transport coupled proton transport | 3 | 789.9× | 4e-08 | MT-CYB, MT-ND4, MT-ND5 |
| response to hypoxia | 6 | 35.9× | 9e-08 | MT-CYB, MT-ND1, MT-ND2, MT-ND4, MT-ND5, MT-CO1 |
| cellular respiration | 3 | 81.0× | 6e-05 | MT-CO3, MT-CYB, MT-CO1 |
| response to copper ion | 2 | 191.5× | 4e-04 | MT-CYB, MT-CO1 |
| response to hyperoxia | 2 | 140.4× | 6e-04 | MT-ATP6, MT-CYB |
| mitochondrial electron transport, cytochrome c to oxygen | 2 | 95.8× | 0.001 | MT-CO3, MT-CO1 |
| response to D-galactosamine | 1 | 1053.2× | 0.005 | MT-CYB |
| cerebellum development | 2 | 44.8× | 0.005 | MT-ND4, MT-CO1 |
| response to cobalamin | 1 | 526.6× | 0.009 | MT-CYB |
| positive regulation of ARF protein signal transduction | 1 | 351.1× | 0.012 | MAPRE2 |
| regulation of mitochondrial ATP synthesis coupled proton transport | 1 | 351.1× | 0.012 | DNAJC30 |
| photoreceptor cell development | 1 | 263.3× | 0.014 | RP1 |
| cellular response to oxygen levels | 1 | 263.3× | 0.014 | NDUFS2 |
| response to ethanol | 2 | 18.3× | 0.018 | MT-CYB, MT-ND4 |
| gliogenesis | 1 | 175.5× | 0.019 | NDUFS2 |
| respiratory chain complex IV assembly | 1 | 150.5× | 0.019 | MT-CO3 |
| response to mercury ion | 1 | 150.5× | 0.019 | MT-CYB |
| response to oxidative stress | 2 | 16.3× | 0.019 | MT-CO1, MT-ND3 |
| response to light intensity | 1 | 131.7× | 0.021 | MT-ND3 |
| mitochondrial ATP synthesis coupled electron transport | 1 | 117.0× | 0.021 | NDUFS2 |
| positive regulation of focal adhesion disassembly | 1 | 117.0× | 0.021 | MAPRE2 |
| positive regulation of non-motile cilium assembly | 1 | 117.0× | 0.021 | RP1 |
| response to hydroperoxide | 1 | 105.3× | 0.021 | MT-ND1 |
| response to glucagon | 1 | 105.3× | 0.021 | MT-CYB |
| retinal rod cell development | 1 | 105.3× | 0.021 | RP1 |
| retinal cone cell development | 1 | 87.8× | 0.023 | RP1 |
Therapeutics
Drugs indicated for this disease
1 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.
| Drug | Development status |
|---|---|
| Idebenone | Approved (phase 4) |
| Curcumin | Phase 3 (in late-stage trials) |
Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Cyclosporine, Elamipretide.
Drug target analysis
Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 18
Druggability breadth: 13 of 18 evidence-associated genes (72%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| PRICKLE3 | 0 | 0 |
| MT-ATP6 | 0 | 0 |
| MT-CO3 | 0 | 0 |
| MT-CYB | 0 | 0 |
| MT-ND1 | 0 | 0 |
| MT-ND2 | 0 | 0 |
| MT-ND4 | 0 | 0 |
| MT-ND4L | 0 | 0 |
| MT-ND5 | 0 | 0 |
| MT-ND6 | 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 |
|---|---|---|
| MT-CO1 | 19 | Binding:12, Functional:4, ADMET:2, Toxicity:1 |
| NDUFS2 | 11 | Binding:10, Functional:1 |
| MT-ND1 | 5 | Binding:5 |
| MT-ND2 | 4 | Binding:4 |
| MT-ND4L | 4 | Binding:4 |
| MT-ND5 | 4 | Binding:4 |
| MT-ND6 | 4 | Binding:4 |
| MT-ND3 | 4 | Binding:4 |
| MT-ATP6 | 1 | Binding:1 |
| MT-CO3 | 1 | Binding:1 |
| RP1 | 1 | Binding:1 |
| MAPRE2 | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| MT-CO1 | 7.1.1.9 | cytochrome-c oxidase |
Pharmacogenomics
Cohort genes with a PharmGKB record: 18; 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 | MT-CO1 |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 17 | PRICKLE3, MT-ATP6, MT-CO3, MT-CYB, MT-ND1, MT-ND2, MT-ND4, MT-ND4L, MT-ND5, MT-ND6 (+7 more) |
Undrugged target profiles
18 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| PRICKLE3 | 0 | — |
| MT-ATP6 | 1 | — |
| MT-CO3 | 1 | — |
| MT-CYB | 0 | — |
| MT-ND1 | 5 | — |
| MT-ND2 | 4 | — |
| MT-ND4 | 0 | — |
| MT-ND4L | 4 | — |
| MT-ND5 | 4 | — |
| MT-ND6 | 4 | — |
| NDUFS2 | 11 | — |
| DNAJC30 | 0 | — |
| RP1 | 1 | — |
| MAPRE2 | 1 | — |
| MT-CO1 | 19 | — |
| MT-ND3 | 4 | — |
| MT-TF | 0 | — |
| MT-TL1 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 21.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 11 |
| PHASE3 | 3 |
| PHASE1/PHASE2 | 3 |
| PHASE1 | 2 |
| PHASE2/PHASE3 | 1 |
| PHASE2 | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT07406854 | PHASE3 | ACTIVE_NOT_RECRUITING | A Phase 3, Multicenter, Randomized, Double-Masked, Sham-Controlled Clinical Trial for Leber’s Hereditary Optic Neuropathy (LHON) Associated With ND4 Mutation |
| NCT03153293 | PHASE2/PHASE3 | UNKNOWN | A Single Intravitreal Injection of rAAV2-ND4 for the Treatment of Leber’s Hereditary Optic Neuropathy |
| NCT03293524 | PHASE3 | COMPLETED | Efficacy & Safety Study of Bilateral IVT Injection of GS010 in LHON Subjects Due to the ND4 Mutation for up to 1 Year |
| NCT03406104 | PHASE3 | COMPLETED | RESCUE and REVERSE Long-term Follow-up |
| NCT05293626 | PHASE1/PHASE2 | ACTIVE_NOT_RECRUITING | Gene Therapy Clinical Trial for the Treatment of Leber’s Hereditary Optic Neuropathy Associated With ND4 Mutations |
| NCT02064569 | PHASE1/PHASE2 | COMPLETED | Safety Evaluation of Gene Therapy in Leber Hereditary Optic Neuropathy (LHON) Patients |
| NCT02176733 | PHASE2 | UNKNOWN | Trial of Cyclosporine in the Acute Phase of Leber Hereditary Optic Neuropathy |
| NCT05820152 | PHASE1/PHASE2 | TERMINATED | Gene Therapy Clinical Trial for the Treatment of Leber’s Hereditary Optic Neuropathy Associated With ND1 Mutations |
| NCT07258667 | PHASE1 | NOT_YET_RECRUITING | Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy |
| NCT02544217 | PHASE1 | COMPLETED | A Dose-escalating Clinical Trial With KH176 |
| NCT01803906 | Not specified | ENROLLING_BY_INVITATION | Tissue Sample Study for Mitochondrial Disorders |
| NCT03011541 | Not specified | RECRUITING | Stem Cell Ophthalmology Treatment Study II |
| NCT03475173 | Not specified | RECRUITING | New Non-invasive Modalities for Assessing Retinal Structure and Function |
| NCT05554835 | Not specified | RECRUITING | Global Registry and Natural History Study for Mitochondrial Disorders |
| NCT06376279 | Not specified | ENROLLING_BY_INVITATION | Genetic Diagnosis in Inborn Errors of Metabolism |
| NCT06682819 | Not specified | RECRUITING | Metabolomics Analysis According to the Retinal Nerve Fiber Layer in Patients With NOHL Mutations (MétabOCT) |
| NCT01267422 | Not specified | COMPLETED | Safety and Efficacy Study of rAAV2-ND4 Treatment of Leber Hereditary Optic Neuropathy (LHON) |
| NCT01892943 | Not specified | COMPLETED | Leber Hereditary Optic Neuropathy (LHON) Historical Case Record Survey |
| NCT03295071 | Not specified | COMPLETED | REALITY LHON Registry |
| NCT03428178 | Not specified | UNKNOWN | Efficacy Study of Gene Therapy for The Treatment of Acute LHON Onset Within Three Months |
| NCT03672968 | Not specified | NO_LONGER_AVAILABLE | EAP_GS010_single Patient |
Drugs tested across these trials (top 30)
| Molecule | Max phase | Trials referencing |
|---|---|---|
| CYCLOSPORINE | 4 | 1 |
| NIACINAMIDE | 4 | 1 |
| SONLICROMANOL | 3 | 1 |