A novel homozygous MSTO1 mutation in Ashkenazi Jewish siblings with ataxia and myopathy.
Adult
Ataxia
/ genetics
Cell Cycle Proteins
/ genetics
Cytoskeletal Proteins
/ genetics
DNA, Mitochondrial
/ metabolism
Female
Fibroblasts
/ metabolism
Homozygote
Humans
Jews
/ genetics
Mitochondria
/ genetics
Muscular Diseases
/ genetics
Mutation, Missense
Pedigree
Phenotype
Siblings
Exome Sequencing
Young Adult
Journal
Journal of human genetics
ISSN: 1435-232X
Titre abrégé: J Hum Genet
Pays: England
ID NLM: 9808008
Informations de publication
Date de publication:
Aug 2021
Aug 2021
Historique:
received:
21
09
2020
accepted:
16
11
2020
revised:
16
11
2020
pubmed:
23
2
2021
medline:
15
12
2021
entrez:
22
2
2021
Statut:
ppublish
Résumé
MSTO1 is a cytoplasmic protein that modulates mitochondrial dynamics by promoting mitochondrial fusion. Mutations in the MSTO1 gene are responsible for an extremely rare condition characterized by early-onset myopathy and cerebellar ataxia. We report here two siblings from a large Ashkenazi Jewish family, presenting with a progressive neuromuscular disease characterized by ataxia and myopathy. By whole exome sequencing, we found a novel homozygous missense mutation (c.1403T>A, p.Leu468Gln) in MSTO1. Studies performed on fibroblasts from the index patient demonstrated the pathogenic role of the identified variant; we found that MSTO1 protein level was reduced and that mitochondrial network was fragmented or formed enlarged structures. Moreover, patient's cells showed reduced mitochondrial DNA amount. Our report confirms that MSTO1 mutations are typically recessive, and associated with clinical phenotypes characterized by early-onset muscle impairment and ataxia, often with upper motor neuron signs and varied cognitive impairment.
Identifiants
pubmed: 33612823
doi: 10.1038/s10038-020-00897-4
pii: 10.1038/s10038-020-00897-4
doi:
Substances chimiques
Cell Cycle Proteins
0
Cytoskeletal Proteins
0
DNA, Mitochondrial
0
MSTO1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
835-840Subventions
Organisme : Fondazione Pierfranco e Luisa Mariani (Pierfranco and Luisa Mariani Foundation)
ID : CM23
Informations de copyright
© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.
Références
Picard M, Wallace DC, Burelle Y. The rise of mitochondria in medicine. Mitochondrion. 2016;30:105–16.
doi: 10.1016/j.mito.2016.07.003
Ferguson SM, De Camilli P. Dynamin, a membrane-remodelling GTPase. Nat Rev Mol Cell Biol. 2012;13:75–88.
doi: 10.1038/nrm3266
Kimura M, Okano Y. Human Misato regulates mitochondrial distribution and morphology. Exp Cell Res. 2007;313:1393–404.
doi: 10.1016/j.yexcr.2007.02.004
Nasca A, Scotton C, Zaharieva I, Neri M, Selvatici R, Magnusson OT, et al. Recessive mutations in MSTO1 cause mitochondrial dynamics impairment, leading to myopathy and ataxia. Hum Mutat. 2017;38:970–7.
doi: 10.1002/humu.23262
Gal A, Balicza P, Weaver D, Naghdi S, Joseph SK, Várnai P, et al. MSTO1 is a cytoplasmic pro-mitochondrial fusion protein, whose mutation induces myopathy and ataxia in humans. EMBO Mol Med. 2017;9:967–84.
doi: 10.15252/emmm.201607058
Iwama K, Takaori T, Fukushima A, Tohyama J, Ishiyama A, Ohba C, et al. Novel recessive mutations in MSTO1 cause cerebellar atrophy with pigmentary retinopathy. J Hum Genet. 2018;63:263–70.
doi: 10.1038/s10038-017-0405-8
Ardicli D, Sarkozy A, Zaharieva I, Deshpande C, Bodi I, Siddiqui A, et al. A novel case of MSTO1 gene related congenital muscular dystrophy with progressive neurological involvement. Neuromuscul Disord. 2019;29:448–55.
doi: 10.1016/j.nmd.2019.03.011
Donkervoort S, Sabouny R, Yun P, Gauquelin L, Chao KR, Hu Y, et al. MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement. Acta Neuropathol. 2019;138:1013–31.
doi: 10.1007/s00401-019-02059-z
Schultz-Rogers L, Ferrer A, Dsouza NR, Zimmermann MT, Smith BE, Klee EW, et al. Novel biallelic variants in MSTO1 associated with mitochondrial myopathy. Cold Spring Harb Mol Case Stud. 2019;5:a004309.
doi: 10.1101/mcs.a004309
Li K, Jin R, Wu X. Whole-exome sequencing identifies rare compound heterozygous mutations in the MSTO1 gene associated with cerebellar ataxia and myopathy. Eur J Med Genet. 2020;63:103623.
doi: 10.1016/j.ejmg.2019.01.013
Shahrour MA, Staretz‐Chacham O, Dayan D, Stephen J, Weech A, Damseh N, et al. Mitochondrial epileptic encephalopathy, 3-methylglutaconic aciduria and variable complex V deficiency associated with TIMM50 mutations. Clin Genet. 2017;91:690–6.
doi: 10.1111/cge.12855
Nasca A, Nardecchia F, Commone A, Semeraro M, Legati A, Garavaglia B, et al. Clinical and biochemical features in a patient with mitochondrial fission factor gene alteration. Front Genet. 2018;9:625.
doi: 10.3389/fgene.2018.00625
Nasca A, Legati A, Baruffini E, Nolli C, Moroni I, Ardissone A, et al. Biallelic mutations in DNM1L are associated with a slowly progressive infantile encephalopathy. Hum Mutat. 2016;37:898–903.
doi: 10.1002/humu.23033
Vidoni S, Zanna C, Rugolo M, Sarzi E, Lenaers G. Why mitochondria must fuse to maintain their genome integrity. Antioxid Redox Signal. 2013;19:379–88.
doi: 10.1089/ars.2012.4800