mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

Summary

mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency (MONDO:0013865) is a disease caused by MTO1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MTO1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 722

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
Mondo ID	MONDO:0013865
OMIM	614702
Orphanet	314637
DOID	DOID:0111480
UMLS	C4749921
MedGen	1664257
GARD	0017428
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation defect type 10 · combined oxidative phosphorylation deficiency 10 · combined oxidative phosphorylation deficiency caused by mutation in MTO1 · combined oxidative phosphorylation deficiency type 10 · COXPD10 · mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency · MTO1 combined oxidative phosphorylation deficiency

Data availability: 722 ClinVar variants · 5 GenCC gene-disease records.

Disease family

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 › combined oxidative phosphorylation deficiency › mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

Genetics & variants

GWAS landscape

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

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

265 uncertain significance, 259 likely benign, 39 pathogenic, 9 conflicting classifications of pathogenicity, 9 likely pathogenic, 7 pathogenic/likely pathogenic, 7 benign/likely benign, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069917	NM_012123.4(MTO1):c.1692del (p.Val565fs)	MTO1	Pathogenic	criteria provided, single submitter
1073223	NM_012123.4(MTO1):c.667C>T (p.Gln223Ter)	MTO1	Pathogenic	criteria provided, single submitter
1073851	NM_012123.4(MTO1):c.734_735del (p.Lys245fs)	MTO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076245	NM_012123.4(MTO1):c.1498C>T (p.Arg500Ter)	MTO1	Pathogenic	criteria provided, single submitter
1328761	NM_012123.4(MTO1):c.402_403del (p.Tyr134_Lys135delinsTer)	MTO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1384098	NM_012123.4(MTO1):c.1750dup (p.Ile584fs)	MTO1	Pathogenic	criteria provided, multiple submitters, no conflicts
1404043	NM_012123.4(MTO1):c.961A>T (p.Lys321Ter)	MTO1	Pathogenic	criteria provided, single submitter
1420202	NM_012123.4(MTO1):c.1789C>T (p.Gln597Ter)	MTO1	Pathogenic	criteria provided, single submitter
1432815	NM_012123.4(MTO1):c.1848T>G (p.Tyr616Ter)	MTO1	Pathogenic	criteria provided, single submitter
1445028	NM_012123.4(MTO1):c.1405C>T (p.Arg469Ter)	MTO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453242	NM_012123.4(MTO1):c.429_444del (p.Asn144fs)	MTO1	Pathogenic	criteria provided, single submitter
1454905	NM_012123.4(MTO1):c.1246del (p.Glu416fs)	MTO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455779	NM_012123.4(MTO1):c.967_968del (p.Leu323fs)	MTO1	Pathogenic	criteria provided, single submitter
1456323	NC_000006.11:g.(?74171578)(74171814_?)del	MTO1	Pathogenic	criteria provided, single submitter
1460431	NC_000006.11:g.(?74171578)(74192363_?)del	MTO1	Pathogenic	criteria provided, single submitter
1979871	NM_012123.4(MTO1):c.1136del (p.Gly379fs)	MTO1	Pathogenic	criteria provided, single submitter
1986427	NM_012123.4(MTO1):c.970del (p.Arg324fs)	MTO1	Pathogenic	criteria provided, single submitter
2016252	NM_012123.4(MTO1):c.724del (p.Arg242fs)	MTO1	Pathogenic	criteria provided, single submitter
2119738	NM_012123.4(MTO1):c.413del (p.Met138fs)	MTO1	Pathogenic	criteria provided, single submitter
2129741	NM_012123.4(MTO1):c.525_526del (p.Val176fs)	MTO1	Pathogenic	criteria provided, single submitter
2150102	NM_012123.4(MTO1):c.1421dup (p.Leu474fs)	MTO1	Pathogenic	criteria provided, single submitter
2150945	NM_012123.4(MTO1):c.1495C>T (p.Gln499Ter)	MTO1	Pathogenic	criteria provided, single submitter
2157351	NM_012123.4(MTO1):c.1643dup (p.Asp549fs)	MTO1	Pathogenic	criteria provided, single submitter
2196399	NM_012123.4(MTO1):c.1451G>A (p.Arg484Gln)	MTO1	Pathogenic	criteria provided, single submitter
2425760	NC_000006.11:g.(?74183068)(74183397_?)del	MTO1	Pathogenic	criteria provided, single submitter
2425763	NC_000006.11:g.(?74175912)(74183397_?)del	MTO1	Pathogenic	criteria provided, single submitter
2425764	NC_000006.11:g.(?74189435)(74192363_?)del	MTO1	Pathogenic	criteria provided, single submitter
2691508	NM_012123.4(MTO1):c.1274del (p.Gly425fs)	MTO1	Pathogenic	criteria provided, single submitter
2718305	NM_012123.4(MTO1):c.137dup (p.His46fs)	MTO1	Pathogenic	criteria provided, single submitter
2832033	NM_012123.4(MTO1):c.648del (p.Gln216fs)	MTO1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
MTO1	Definitive	Autosomal recessive	mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTO1	Orphanet:314637	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTO1	HGNC:19261	ENSG00000135297	Q9Y2Z2	5-taurinomethyluridine-[tRNA] synthase subunit MTO1, mitochondrial	gencc,clinvar
EEF1A1	HGNC:3189	ENSG00000156508	P68104	Elongation factor 1-alpha 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTO1	5-taurinomethyluridine-[tRNA] synthase subunit MTO1, mitochondrial	Component of the GTPBP3-MTO1 complex that catalyzes the 5-taurinomethyluridine (taum(5)U) modification at the 34th wobble position (U34) of mitochondrial tRNAs (mt-tRNAs), which plays a role in mt-tRNA decoding and mitochondrial translatio…
EEF1A1	Elongation factor 1-alpha 1	Translation elongation factor that catalyzes the GTP-dependent binding of aminoacyl-tRNA (aa-tRNA) to the A-site of ribosomes during the elongation phase of protein synthesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTO1	Other/Unknown	no		MnmG-rel, MnmG-rel_CS, MnmG_C
EEF1A1	Other/Unknown	no		T_Tr_GTP-bd_dom, EFTu-like_2, Transl_elong_EF1A_euk/arc

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	1
germinal epithelium of ovary	1
sperm	1
embryo	1
stromal cell of endometrium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTO1	284	ubiquitous	marker	germinal epithelium of ovary, sperm, endothelial cell
EEF1A1	273	ubiquitous	marker	stromal cell of endometrium, embryo, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTO1	2,309
EEF1A1	1,455

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EEF1A1	P68104	17

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTO1	Q9Y2Z2	85.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

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

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
tRNA modification in the mitochondrion	1	519.1×	0.010	MTO1
Protein methylation	1	335.9×	0.010	EEF1A1
Chaperone Mediated Autophagy	1	248.3×	0.010	EEF1A1
HSF1 activation	1	190.3×	0.010	EEF1A1
tRNA processing	1	178.4×	0.010	MTO1
SARS-CoV-1 modulates host translation machinery	1	154.3×	0.010	EEF1A1
Eukaryotic Translation Elongation	1	139.3×	0.010	EEF1A1
Peptide chain elongation	1	63.4×	0.020	EEF1A1
Metabolism of RNA	1	20.8×	0.053	MTO1
Neutrophil degranulation	1	11.5×	0.085	EEF1A1

GO biological processes by enrichment

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

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial tRNA wobble uridine modification	1	4213.0×	0.002	MTO1
regulation of chaperone-mediated autophagy	1	1685.2×	0.002	EEF1A1
host-mediated activation of viral genome replication	1	842.6×	0.003	EEF1A1
translational elongation	1	601.9×	0.003	EEF1A1
tRNA methylation	1	290.6×	0.005	MTO1
cellular response to epidermal growth factor stimulus	1	159.0×	0.007	EEF1A1
translation	1	51.4×	0.019	EEF1A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTO1	0	0
EEF1A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EEF1A1	15	Binding:15

Pharmacogenomics

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

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

Chemical tractability of cohort targets

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MTO1, EEF1A1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MTO1	0	—
EEF1A1	15	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.