MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement

Care4Rare Canada Consortium

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23 Scopus citations


MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype–phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Original languageEnglish (US)
Pages (from-to)1013-1031
Number of pages19
JournalActa Neuropathologica
Issue number6
StatePublished - Dec 1 2019

Bibliographical note

Funding Information:
The work in C.G. Bönnemann’s laboratory is supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke. The work in T.E. Shutt’s laboratory is supported by funds provided by the Alberta Children’s Hospital Research Institute, the Alberta Children’s Hospital Foundation, and National Sciences and Engineering Research Council of Canada (NSERC). Exome sequencing was partially funded through the Clinical Center Genomics Opportunity, which is sponsored by the National Human Genome Research Institute, the NIH Deputy Director for Intramural Research and the NIH Clinical Center. Sequencing analysis was provided by the Broad Center for Mendelian Genomics (UM1 HG008900), which is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. Part of this work was also performed under the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute (OGI-147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Quebec and Children’s Hospital of Eastern Ontario Foundation. Dr. Moore is partially supported by NIH funding of the Iowa Wellstone Muscular Dystrophy Cooperative Research Center, U54, NS053672. R.S. is a recipient of a Queen Elizabeth II Graduate Scholarship and Alberta Children’s Hospital Research Institute Graduate Studentship.

Publisher Copyright:
© 2019, The Author(s).


  • Cerebellar atrophy
  • MSTO1
  • Mitochondrial fusion
  • MtDNA depletion
  • Muscular dystrophy


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