MTO1

protein-coding

mitochondrial tRNA translation optimization 1

Gene summary

This gene encodes a mitochondrial protein thought to be involved in mitochondrial tRNA modification. The encoded protein may also play a role in the expression of the non-syndromic and aminoglycoside-induced deafness phenotypes associated with a specific mutation in the mitochondrial 12S rRNA gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_012123.4

Inheritance

ClinVar variants

P:82U:348B:211

Top phenotype

Combined oxidative phosphorylation deficiency 10

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr6:73,461,578-73,509,236

External References & Databases

Ensembl (ENSG00000135297)

Transcript & Mutation Effects

hg38 • Region Span ~47.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013865

Submitter: PanelApp Australia

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MTO1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 4, 2024. The *MTO1* gene encodes mitochondrial tRNA translation optimization 1, which increases the accuracy and efficiency of mitochondrial DNA (mtDNA) translation by catalyzing the 5-carboxymethylaminomethylation of the wobble uridine base in three mitochondrial tRNAs (mt-tRNAs: tRNA-Gln, tRNA-Glu, and tRNA-Lys). The *MTO1* gene was first reported in relation to primary mitochondrial disease in 2012 (Ghezzi et al. (2012) PMID: 22608499. The condition was first described in a family from northern Italy in two siblings with infantile hypertrophic cardiomyopathy and lactic acidosis. Subsequent publications have reported a consistently early onset disease characterized by lactic acidosis, hypertrophic cardiomyopathy and mild to severe global developmental delay. Phenotypic heterogeneity is observed with additional features such as feeding difficulties, optic atrophy, seizures and ataxia. Variability is reported in the severity of disease with many probands not surviving infancy while other affected individuals reached adolescence and early adulthood. While various names could be given to the constellation of features seen in those with *MTO1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MTO1* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 10 unique variants reported in nine cases from five publications (PMIDs: 22608499, 23929671, 25058219, 29331171, 34547275). Variants included three frameshift, one nonsense, and six missense, one of which, c.1232C>T (p.Thr411Ile) is a proposed founder variant in the Pakistani population (PMID: 25058219). The maximum score for case-level data was reached in this curation; however we note that, in total, there appear to be at least 42 affected individuals reported in the medical literature. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease. Mouse and zebrafish models recapitulate aspects of the cardiovascular phenotype associated with disease, together with altered mitochondrial morphology and biochemistry (PMIDs: 33340416, 25506927, 33836087). In summary, there is definitive evidence to support the relationship between *MTO1* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 4, 2024 (SOP Version 10).

mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiencySUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0013865

Submitter: Orphanet

mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013865

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013865

Submitter: Ambry Genetics

mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013865

Submitter: G2P

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 10AR

Manifestation: Biochemical; Cardiovascular; Neurologic

Intervention: Biochemical

Rationale: The condition can include findings such as hypertrophic cardiomyopathy, hypoglycemia, and and lactic acidosis; Treatment with biotin, coenzyme Q10, thiamine, and dichloroacetate has been reported as beneficial in multiple individuals

Comments: Biochemical treatments (eg, with a mitochondrial cocktail) and ketogenic diet have been described, but the efficacy has been reported as unclear

Refs: 22608499; 23929671; 29331171

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MTO1 variants in ClinVar

11 Conditions Cataloged

Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiencyTotal: 705

not providedTotal: 130

Inborn genetic diseasesTotal: 107

not specifiedTotal: 47

MTO1-related disorderTotal: 40

Fetal anomalies with a likely genetic causeTotal: 3

Abnormal brain morphologyTotal: 2

Mitochondrial oxidative phosphorylation disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012123.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	194 clinvar		197
missense	3 clinvar	18 clinvar	334 clinvar	17 clinvar		372
nonsense	11 clinvar	7 clinvar	3 clinvar			21
start loss						0
frameshift	30 clinvar	9 clinvar	5 clinvar			44
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	3 clinvar			7
Total	45	37	348	211	0	641

Highest pathogenic variant AF is 0.0001480738

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 99 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012123.4	RefSeq	NP_036255.2	12	MANE Select
ENST00000498286.6	Ensembl	ENSP00000419561.2	12	MANE Select
NM_001123226.2	RefSeq	NP_001116698.1	13	Standard
NM_133645.3	RefSeq	NP_598400.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

tRNA wobble uridine modification
tRNA methylation
mitochondrial tRNA wobble uridine modification

Molecular Function

RNA binding
flavin adenine dinucleotide binding

Cellular Component

mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000415954
Coding exons: 13
Length: 47659
Individuals with no LoFs: 125644
Homozygous LoFs: 0
Heterozygous LoFs: 103
Defined: 125747
p: 0.000410

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.650	373	410	0.910	0.0000225	4722
Missense (PolyPhen)		169	194.53	0.86877		2038
Synonymous	0.538	139	147	0.944	0.00000759	1472
Loss of Function	3.25	15	36.1	0.416	0.00000222	408

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00049	0.00049	rare
Ashkenazi Jewish	0.0015	0.0015	notable
East Asian	0.00044	0.00044	rare
Finnish	0.00051	0.00051	rare
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.00052	0.00052	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the 5-carboxymethylaminomethyl modification (mnm(5)s(2)U34) of the wobble uridine base in mitochondrial tRNAs. {ECO:0000269|PubMed:12011058}.;

Recessive Scores

pRec: 0.161

Intolerance Scores

LoFtool: 0.0935
RVIS EVS: -0.2
RVIS percentile EVS: 39.17

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.154

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium