MTO1 – Mitochondrial Disease

Mitochondrial tRNA translation optimization 1 (MTO1) encodes a conserved mitochondrial tRNA modifier essential for oxidative phosphorylation. Biallelic MTO1 variants cause combined oxidative phosphorylation deficiency type 10 (COXPD10), manifesting as lactic acidosis, cardiomyopathy, developmental delay, and hypotonia in infancy (PMID:29331171). The disorder follows an autosomal recessive inheritance pattern, with molecular confirmation required for diagnosis.

Genetic evidence includes 35 unrelated probands harboring MTO1 variants, encompassing 15 missense and 3 frameshift mutations with one splice-site change, none resulting in complete loss of function (PMID:29331171). Reported recurrent LoF alleles and missense changes such as c.1055C>T (p.Thr352Met) have been observed in multiple cohorts, including Chinese and European ancestries. Founder haplotypes have been suggested for certain recurrent variants identified by exome sequencing in large mitochondrial disease series (PMID:25058219).

Segregation studies demonstrate co-segregation of pathogenic alleles in affected sibships. In one report, two affected siblings carried compound heterozygous MTO1 variants with consistent clinical presentations (PMID:29331171).

Functional assays in yeast and zebrafish models confirm a loss-of-function mechanism: patient-derived missense mutations impair oxidative growth, mitochondrial translation, and complex IV activity in yeast, with wild-type MTO1 rescuing defects in fibroblasts (PMID:23929671). mto1 knockout zebrafish exhibit impaired mitochondrial tRNA taurine modification, decreased OXPHOS complex activities, and hypertrophic cardiomyopathy phenocopying human disease (PMID:33836087).

No studies have refuted the MTO1–mitochondrial disease relationship. Targeted sequencing approaches occasionally yield variants of uncertain significance in MTO1 without clear phenotypic correlation, underscoring the importance of comprehensive functional validation (PMID:22494076).

In summary, autosomal recessive MTO1 deficiency is a well‐established cause of early‐onset mitochondrial disease characterized by lactic acidosis, cardiomyopathy, and neurodevelopmental impairment. Functional and genetic data strongly support pathogenicity of biallelic MTO1 variants. Molecular diagnosis enables precision management and genetic counseling.

Key Take-home: Biallelic MTO1 variants underlie a treatable mitochondrial encephalomyopathy with characteristic cardiomyopathy and lactic acidosis; genetic confirmation guides therapy and family planning.

References

• Molecular Genetics and Metabolism • 2018 • The genotypic and phenotypic spectrum of MTO1 deficiency PMID:29331171
• Human Mutation • 2013 • MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast PMID:23929671
• Nucleic Acids Research • 2021 • Ablation of Mto1 in zebrafish exhibited hypertrophic cardiomyopathy manifested by mitochondrion RNA maturation deficiency PMID:33836087
• JAMA • 2014 • Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies PMID:25058219
• Pediatrics International • 2012 • Next-generation sequencing for mitochondrial diseases: a wide diagnostic spectrum PMID:22494076

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