Recessive mutations in MSTO1 cause mitochondrial dynamics impairment, leading to myopathy and ataxia

Abstract

We report here the first families carrying recessive variants in the MSTO1 gene: compound heterozygous mutations were identified in two sisters and in an unrelated singleton case, who presented a multisystem complex phenotype mainly characterized by myopathy and cerebellar ataxia. Human MSTO1 is a poorly studied protein, suggested to have mitochondrial localization and to regulate morphology and distribution of mitochondria. As for other mutations affecting genes involved in mitochondrial dynamics, no biochemical defects typical of mitochondrial disorders were reported. Studies in patients’ fibroblasts revealed that MSTO1 protein levels were strongly reduced, the mitochondrial network was fragmented, and the fusion events among mitochondria were decreased, confirming the deleterious effect of the identified variants and the role of MSTO1 in modulating mitochondrial dynamics. We also found that MSTO1 is mainly a cytosolic protein. These findings indicate recessive mutations in MSTO1 as a new cause for inherited neuromuscular disorders with multisystem features.

Mitochondrial dynamics: overview of molecular mechanisms

“…MSTO1 (Misato) is a cytoplasmic regulator of the OMM fusion machinery since it depletion leads to impaired fusion [ 27 , 28 ]. Finally, the reactive oxygen species modulator 1 (ROMO1) protein has been identified as a redox-regulated protein required for mitochondrial fusion and normal cristae morphology [ 53 ].…”

“…The relevance of mitochondrial dynamics has also been highlighted in humans where pathogenic mutations in genes corresponding to the core fission machinery (Drp1 [ 20 ], Dnm2 [ 21 ], MFF [ 22 ] and Mid49 [ 23 ]), fusion (Mfn2 [ 24 ] and OPA1 [ 25 , 26 ]), and other factors involved in these events (e.g. MSTO1 [ 27 , 28 ], GDAP1 [ 29 ] and SLC25A46 [ 30 , 31 ]) have been reported.…”

Clinical-genetic features and peculiar muscle histopathology in infantileDNM1L-related mitochondrial epileptic encephalopathy

“…Better known clinical conditions that occur more frequently are related to defects in factors that are conversely implicated in mitochondrial membrane fusion such as Charcot–Marie–Tooth disease type 2A caused by dominant or recessive mutations in MFN2 (mitofusin 2; MIM #608507), and optic atrophy or Leigh‐like infantile encephalopathies caused by dominant or recessive mutations in OPA1 (MIM #605290). Additional rare neurological phenotypes of “optic atrophy plus” syndrome and 3‐methylglutaconic aciduria or cataracts are related to recessive or dominant mutations in OPA3 (MIM #606580), a factor involved in mitochondrial shaping; a mild Charcot–Marie–Tooth disease type 2K is caused by biallelic recessive mutations in GDAP1 (MIM #606598), that encodes for a mitochondrial protein involved in mitochondrial dynamics; and finally mitochondrial myopathy and ataxia have been recently reported to be due to dominant or recessive mutations in MSTO1 (MIM #617619), encoding a cytoplasmic promitochondrial fusion protein (Nasca, Scotton et al, ).…”

Myopathology of Adult and Paediatric Mitochondrial Diseases

“…Serum CK ranges from normal to moderate elevation, and biopsies show myopathic or dystrophic changes, without histochemical and biochemical RC OXPHOS deficiency. Reduced levels of MSTO1 mRNA and protein in fibroblasts is associated with abnormalities of the mitochondrial network including fragmentation, aggregation, decreased network continuity and fusion activity, pointing to a putative role for MSTO1 in mitochondrial morphogenesis by regulating mitochondrial fusion, and loss-of-function mutations linked to a multisystem mitochondrial disease [ 132 , 133 ]. Defects in CHKB , MICU1 and MSTO1 are examples of novel pathomechanisms and overlapping clinicopathological features involving muscular dystrophy, lipid metabolism, congenital myopathy and mitochondrial biology, with unique and recognizable muscle pathology signatures in absence of primary OXPHOS defects involving the RCE.…”