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

Hum Mutat. 2017 Aug;38(8):970-977. doi: 10.1002/humu.23262.

Alessia Nasca ¹, Chiara Scotton ², Irina Zaharieva ³, Marcella Neri ², Rita Selvatici ², Olafur Thor Magnusson ⁴, Aniko Gal ⁵ ⁶, David Weaver ⁵, Rachele Rossi ², Annarita Armaroli ², Marika Pane ⁷, Rahul Phadke ³, Anna Sarkozy ³, Francesco Muntoni ³, Imelda Hughes ⁸, Antonella Cecconi ⁹, György Hajnóczky ⁵, Alice Donati ¹⁰, Eugenio Mercuri ⁷, Massimo Zeviani ¹¹, Alessandra Ferlini ² ³, Daniele Ghezzi ¹

Affiliations

1 Molecular Neurogenetics Unit, Foundation IRCCS Neurological Institute Besta, Milan, Italy.
2 Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
3 Dubowitz Neuromuscular Centre, UCL Great Ormond Street Hospital, London, UK.
4 deCODE Genetics, Reykjavik, Iceland.
5 MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
6 Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary.
7 Neuropsichiatry Unit, Catholic University, Policlinico Gemelli, Rome, Italy.
8 Royal Manchester Children's Hospital, Manchester, UK.
9 Pediatrics Medical Genetics, Hospital S. Maria Annunziata Bagno a Ripoli, Florence, Italy.
10 Unit of Metabolic and Muscular Diseases, Meyer Children Hospital, Florence, Italy.
11 Mitochondrial Biology Unit - MRC, Cambridge, UK.

PMID: 28544275 DOI: 10.1002/humu.23262

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.

Keywords

MSTO1; ataxia; mitochondrial dynamics; myopathy; skeletal abnormalities.

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