MSTO1 – Mitochondrial Disease

Misato homolog 1 (MSTO1) encodes a cytosolic protein that regulates mitochondrial fusion and distribution (HGNC:29678). Biallelic MSTO1 variants cause an autosomal recessive mitochondrial disorder (MONDO:0044970) featuring early-onset myopathy, cerebellar ataxia, and multisystem involvement.

To date, eleven probands from seven unrelated families have been reported with MSTO1-related mitochondrial disease (PMID:28544275; PMID:31604776; PMID:30684668; PMID:33612823; PMID:36468072; PMID:36035138). All affected individuals harbor compound heterozygous or homozygous variants consistent with autosomal recessive inheritance, with segregation confirmed in four multiplex families ([PMID:28544275]; [PMID:30684668]; [PMID:33612823]; [PMID:36468072]).

Reported variants include 19 missense, nine loss-of-function (nonsense, frameshift, or splice-site), and large multi-exon deletions across exons 1–14, without evidence for founder alleles. An exemplar pathogenic allele is c.651C>G (p.Phe217Leu) ([PMID:31604776]).

Affected individuals present with muscle weakness (HP:0001324), hypotonia (HP:0001252), scoliosis (HP:0002650), pectus excavatum (HP:0000767), dysphagia (HP:0002015), and restrictive ventilatory defect (HP:0002091). Additional features include cerebellar ataxia, elevated serum creatine kinase, and neurodevelopmental delay.

Functional analyses in patient fibroblasts demonstrate markedly reduced MSTO1 protein levels and fragmented mitochondrial networks with decreased fusion events ([PMID:28544275]) and reduced mtDNA content ([PMID:36468072]), confirming loss-of-function as the predominant mechanism.

Collectively, the genetic and experimental data fulfill ClinGen criteria for a strong gene–disease relationship under an autosomal recessive model. No conflicting evidence has been reported for MSTO1 in mitochondrial disease.

Key Take-home: MSTO1 biallelic loss-of-function variants cause a reproducible mitochondrial myopathy syndrome, informing molecular diagnosis and potential therapeutic targeting of mitochondrial fusion pathways.

References

• Human mutation • 2017 • Recessive mutations in MSTO1 cause mitochondrial dynamics impairment, leading to myopathy and ataxia. PMID:28544275
• Cold Spring Harbor molecular case studies • 2019 • Novel biallelic variants in MSTO1 associated with mitochondrial myopathy. PMID:31604776
• European journal of medical genetics • 2020 • Whole-exome sequencing identifies rare compound heterozygous mutations in the MSTO1 gene associated with cerebellar ataxia and myopathy. PMID:30684668
• Journal of human genetics • 2021 • A novel homozygous MSTO1 mutation in Ashkenazi Jewish siblings with ataxia and myopathy. PMID:33612823
• Frontiers in neurology • 2022 • Indentification of novel MSTO1 compound heterozygous mutations in a Chinese family with recessive cerebellar atrophy and ataxia. PMID:36468072
• Frontiers in genetics • 2022 • Case Report: Evidences of myasthenia and cerebellar atrophy in a chinese patient with novel compound heterozygous MSTO1 variants. PMID:36035138

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