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Acta Neuropathol. 2019 Dec;138(6):1013-1031. doi: 10.1007/s00401-019-02059-z. Epub 2019 Aug 29.

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

Author information

1
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
2
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada.
3
Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
4
Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
5
Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA, USA.
6
John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
7
Department of Pathology Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.
8
Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
9
Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia.
10
Department of Neurology, Sydney Children's Hospital, Sydney, NSW, Australia.
11
UNSW Sydney, School of Women's and Children's Health, Sydney, NSW, Australia.
12
Research for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
13
Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China.
14
School of Biomedical Science, The University of Hong Kong, Hong Kong SAR, China.
15
Oregon Health and Science University, Neuromuscular Program, Doernbecher Children's Hospital, Portland, OR, USA.
16
Department of Neurology, University of Minnesota, Minneapolis, MN, USA.
17
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, USA.
18
Department of Neurology, Virginia Commonwealth University, Children's Hospital of Richmond at VCU, Richmond, VA, USA.
19
Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
20
Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, USA.
21
Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, USA.
22
University of Missouri-Kansas City School of Medicine, Kansas City, USA.
23
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
24
Department of Medical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia.
25
Department of Neurology, University Hospital Rigshospitalet, Copenhagen, Denmark.
26
Department of Pediatrics, Children's Mercy Hospital, Kansas City, USA.
27
Division of Neurology, Children's Mercy Hospital, Kansas City, USA.
28
GeneDx, Gaithersburg, MD, USA.
29
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
30
Care4Rare Research Consortium, Ottawa, Canada.
31
Departments of Pediatrics, Section of Neurology, University of Calgary, Calgary, AB, Canada.
32
Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
33
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Carsten.bonnemann@nih.gov.
34
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada. timothy.shutt@ucalgary.ca.
35
Department of Medical Genetics, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada. timothy.shutt@ucalgary.ca.

Abstract

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.

KEYWORDS:

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

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