Mitochondrial non-syndromic sensorineural hearing loss

Summary

Mitochondrial non-syndromic sensorineural hearing loss (MONDO:0010779) is a disease with 7 cohort genes. The dominant Reactome pathway is Mitochondrial translation termination (3 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 7
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial non-syndromic sensorineural hearing loss
Mondo ID	MONDO:0010779
OMIM	500008
Orphanet	90641
DOID	DOID:0111751
UMLS	C3151897
MedGen	463247
GARD	0016792
Is cancer (heuristic)	no

Also known as: deafness, isolated, due to mitochondrial transmission · isolated mitochondrial neurosensory deafness · isolated mitochondrial sensorineural deafness · mitochondrial non-syndromic neurosensory deafness · mitochondrial non-syndromic sensorineural deafness

Data availability: 20 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

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 › mitochondrial oxidative phosphorylation disorder › mitochondrial non-syndromic sensorineural hearing loss

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

Subtypes (1): hearing loss, sensorineural, autosomal-mitochondrial type

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

20 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 3 likely pathogenic, 3 likely benign, 2 pathogenic, 1 benign, 1 pathogenic; drug response, 1 drug response, 1 likely pathogenic; drug response, 1 uncertain significance; drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
9563	NC_012920.1(MT-TS1):m.7445A>G	MT-CO1	Pathogenic	reviewed by expert panel
9628	NC_012920.1(MT-RNR1):m.1555A>G	MT-ND1	Pathogenic; drug response	reviewed by expert panel
42226	NC_012920.1(MT-TS1):m.7471dup	MT-TS1	Pathogenic	reviewed by expert panel
9632	NC_012920.1(MT-RNR1):m.1494C>T	MT-RNR1	Likely pathogenic; drug response	reviewed by expert panel
30004	NC_012920.1(MT-TH):m.12201T>C	MT-TH	Likely pathogenic	reviewed by expert panel
9565	NC_012920.1(MT-TS1):m.7510T>C	MT-TS1	Likely pathogenic	reviewed by expert panel
9566	NC_012920.1(MT-TS1):m.7511T>C	MT-TS1	Likely pathogenic	reviewed by expert panel
9631	NC_012920.1(MT-RNR1):m.1095T>C	MT-RNR1	drug response	reviewed by expert panel
9634	NC_012920.1(MT-RNR1):m.827A>G	MT-RNR1	Uncertain significance; drug response	criteria provided, multiple submitters, no conflicts
40158	NC_012920.1(MT-CO1):m.7443A>G	MT-CO1	Uncertain significance	reviewed by expert panel
631469	NC_012920.1(MT-TS1):m.7445A>T	MT-CO1	Uncertain significance	reviewed by expert panel
9568	NC_012920.1(MT-TS1):m.7445A>C	MT-CO1	Uncertain significance	reviewed by expert panel
139642	Single allele	MT-RNR1	Uncertain significance	no assertion criteria provided
9603	NC_012920.1(MT-TI):m.4295A>G	MT-TI	Uncertain significance	reviewed by expert panel
40885	NC_012920.1(MT-TS1):m.7505T>C	MT-TS1	Uncertain significance	reviewed by expert panel
631470	NC_012920.1(MT-TS1):m.7462C>T	MT-TS1	Uncertain significance	reviewed by expert panel
9663	NC_012920.1(MT-CO1):m.7444G>A	MT-CO1	Likely benign	reviewed by expert panel
29998	NC_012920.1(MT-ND1):m.3388C>A	MT-ND1	Benign	criteria provided, multiple submitters, no conflicts
9630	NC_012920.1(MT-RNR1):m.1291T>C	MT-RNR1	Likely benign	criteria provided, single submitter
9633	NC_012920.1(MT-RNR1):m.961T>G	MT-RNR1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 22 · 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
POU3F4	Definitive	X-linked	nonsyndromic genetic hearing loss	5
MT-CO1	Supportive	Mitochondrial	mitochondrial non-syndromic sensorineural hearing loss	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
POU3F4	Orphanet:1435	Xq21 microdeletion syndrome
POU3F4	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
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-RNR1	Orphanet:551	MERRF
MT-RNR1	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-TH	Orphanet:550	MELAS
MT-TH	Orphanet:551	MERRF
MT-TH	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-TI	Orphanet:620371	Gitelman-like kidney tubulopathy due to mitochondrial DNA mutation
MT-TS1	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
MT-TS1	Orphanet:550	MELAS
MT-TS1	Orphanet:551	MERRF
MT-TS1	Orphanet:663	Mitochondrial DNA-related progressive external ophthalmoplegia
MT-TS1	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness

Cohort genes → proteins

7 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MT-CO1	HGNC:7419	ENSG00000198804	P00395	Cytochrome c oxidase subunit 1	gencc,clinvar
POU3F4	HGNC:9217	ENSG00000196767	P49335	POU domain, class 3, transcription factor 4	gencc
MT-ND1	HGNC:7455	ENSG00000198888	P03886	NADH-ubiquinone oxidoreductase chain 1	clinvar
MT-RNR1	HGNC:7470	ENSG00000211459	A0A0C5B5G6	Mitochondrial-derived peptide MOTS-c	clinvar
MT-TH	HGNC:7487	ENSG00000210176		mitochondrially encoded tRNA-His (CAU/C)	clinvar
MT-TI	HGNC:7488	ENSG00000210100		mitochondrially encoded tRNA-Ile (AUU/C)	clinvar
MT-TS1	HGNC:7497	ENSG00000210151		mitochondrially encoded tRNA-Ser (UCN) 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
POU3F4	POU domain, class 3, transcription factor 4	Probable transcription factor which exert its primary action widely during early neural development and in a very limited set of neurons in the mature brain.
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-RNR1	Mitochondrial-derived peptide MOTS-c	Regulates insulin sensitivity and metabolic homeostasis.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 5 · Druggable fraction: 0.14

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	1.7×	0.595
Other/Unknown	5	1.3×	0.595
Transcription factor	1	1.2×	0.595

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MT-CO1	Enzyme (other)	yes	7.1.1.9	Cyt_C_Oxase_1, Cyt_c_Oxase_su1_BS, Cyt_c_oxase-like_su1_dom
POU3F4	Transcription factor	no		POU_dom, HD, Homeodomain-like_sf
MT-ND1	Other/Unknown	no		NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS
MT-RNR1	Other/Unknown	no		MT-RNR1
MT-TH	Other/Unknown	no
MT-TI	Other/Unknown	no
MT-TS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
apex of heart	2
putamen	2
sural nerve	2
rectum	1
stromal cell of endometrium	1
ganglionic eminence	1
nucleus accumbens	1
ventricular zone	1
adipose tissue	1
frontal cortex	1
gastrocnemius	1
monocyte	1
prefrontal cortex	1
skeletal muscle tissue	1
duodenum	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MT-CO1	134	ubiquitous	marker	granulocyte, stromal cell of endometrium, rectum
POU3F4	54	broad	yes	ganglionic eminence, ventricular zone, nucleus accumbens
MT-ND1	134	ubiquitous	marker	adipose tissue, gastrocnemius, frontal cortex
MT-RNR1	134	ubiquitous	marker	granulocyte, monocyte, prefrontal cortex
MT-TH	118	broad	yes	sural nerve, apex of heart, putamen
MT-TI	117	broad	yes	skeletal muscle tissue, sural nerve, putamen
MT-TS1	118	tissue_specific	yes	duodenum, apex of heart, vermiform appendix

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MT-CO1	3,547
MT-ND1	3,537
POU3F4	1,132
MT-RNR1	4
MT-TH	0
MT-TI	0
MT-TS1	0

Intra-cohort edges

A	B	Sources
MT-CO1	MT-ND1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MT-ND1	P03886	5
MT-CO1	P00395	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MT-RNR1	A0A0C5B5G6	72.00
POU3F4	P49335	64.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 7 evidence-associated genes (3 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 3 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	3	109.8×	1e-05	MT-CO1, MT-ND1, MT-RNR1
Mitochondrial protein degradation	2	76.1×	0.002	MT-CO1, MT-ND1
Respiratory electron transport	2	63.4×	0.002	MT-CO1, MT-ND1
FASTK family proteins regulate processing and stability of mitochondrial RNAs	1	951.7×	0.004	MT-RNR1
tRNA processing in the mitochondrion	1	761.3×	0.004	MT-RNR1
Mitochondrial RNA degradation	1	543.8×	0.005	MT-RNR1
rRNA processing in the mitochondrion	1	423.0×	0.005	MT-RNR1
rRNA modification in the mitochondrion	1	292.8×	0.006	MT-RNR1
Complex IV assembly	1	76.1×	0.022	MT-CO1
Cytoprotection by HMOX1	1	61.4×	0.024	MT-CO1
Complex I biogenesis	1	55.2×	0.024	MT-ND1
TP53 Regulates Metabolic Genes	1	43.3×	0.024	MT-CO1
Mitochondrial translation initiation	1	42.3×	0.024	MT-RNR1
Mitochondrial translation elongation	1	42.3×	0.024	MT-RNR1
Mitochondrial ribosome-associated quality control	1	40.9×	0.024	MT-RNR1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
aerobic respiration	2	123.9×	0.002	MT-CO1, MT-ND1
response to hypoxia	2	47.9×	0.008	MT-CO1, MT-ND1
skeletal muscle tissue growth	1	702.2×	0.008	MT-RNR1
negative regulation of mesenchymal cell apoptotic process	1	601.9×	0.008	POU3F4
response to hydroperoxide	1	421.3×	0.008	MT-ND1
activation of protein kinase activity	1	383.0×	0.008	MT-RNR1
response to copper ion	1	383.0×	0.008	MT-CO1
osteoblast proliferation	1	351.1×	0.008	MT-RNR1
positive regulation of protein serine/threonine kinase activity	1	324.1×	0.008	MT-RNR1
respiratory electron transport chain	1	210.7×	0.011	MT-CO1
mitochondrial electron transport, cytochrome c to oxygen	1	191.5×	0.011	MT-CO1
response to electrical stimulus	1	162.0×	0.012	MT-CO1
cochlea morphogenesis	1	145.3×	0.013	POU3F4
cellular respiration	1	108.0×	0.016	MT-CO1
mitochondrial respiratory chain complex I assembly	1	102.8×	0.016	MT-ND1
mitochondrial electron transport, NADH to ubiquinone	1	89.6×	0.016	MT-ND1
cerebellum development	1	89.6×	0.016	MT-CO1
proton motive force-driven mitochondrial ATP synthesis	1	65.8×	0.020	MT-ND1
response to oxidative stress	1	32.7×	0.038	MT-CO1
osteoblast differentiation	1	30.3×	0.039	MT-RNR1
sensory perception of sound	1	25.2×	0.043	POU3F4
regulation of transcription by RNA polymerase II	2	5.8×	0.043	MT-RNR1, POU3F4
brain development	1	19.9×	0.052	POU3F4
response to xenobiotic stimulus	1	17.3×	0.057	MT-ND1
regulation of carbohydrate utilization	1	—	—	MT-RNR1
purine-containing compound biosynthetic process	1	—	—	MT-RNR1
negative regulation of phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity	1	—	—	MT-RNR1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 2 of 7 evidence-associated genes (29%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MT-CO1	0	0
POU3F4	0	0
MT-ND1	0	0
MT-RNR1	0	0
MT-TH	0	0
MT-TI	0	0
MT-TS1	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
MT-ND1	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MT-CO1	7.1.1.9	cytochrome-c oxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
MT-RNR1	1

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	6	POU3F4, MT-ND1, MT-RNR1, MT-TH, MT-TI, MT-TS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MT-CO1	19	—
POU3F4	0	—
MT-ND1	5	—
MT-RNR1	0	—
MT-TH	0	—
MT-TI	0	—
MT-TS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.