Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

A novel homozygous MSTO1 mutation in Ashkenazi Jewish siblings with ataxia and myopathy

Journal of Human Genetics volume 66, pages 835–840 (2021)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

References

  1. Picard M, Wallace DC, Burelle Y. The rise of mitochondria in medicine. Mitochondrion. 2016;30:105–16.

    Article  CAS  Google Scholar 

  2. Ferguson SM, De Camilli P. Dynamin, a membrane-remodelling GTPase. Nat Rev Mol Cell Biol. 2012;13:75–88.

    Article  CAS  Google Scholar 

  3. Kimura M, Okano Y. Human Misato regulates mitochondrial distribution and morphology. Exp Cell Res. 2007;313:1393–404.

    Article  CAS  Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. 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.

    Article  CAS  Google Scholar 

  7. 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.

    Article  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    Article  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This project was carried out in the Center for the Study of Mitochondrial Pediatric Diseases funded by the Mariani Foundation. DG is a member of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD).

Author information

Authors and Affiliations

  1. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126, Milan, Italy

    Alessia Nasca, Ivano Di Meo & Daniele Ghezzi

  2. Department of Pathology, Hadassah Hebrew University of Jerusalem, 91120, Jerusalem, Israel

    Yakov Fellig

  3. Department of Genetics, Hadassah Hebrew University of Jerusalem, 91120, Jerusalem, Israel

    Ann Saada & Orly Elpeleg

  4. Department of Pathophysiology and Transplantation, University of Milan, 20122, Milan, Italy

    Daniele Ghezzi

  5. Pediatric Neurology Unit, Hadassah Hebrew University of Jerusalem, 91240, Jerusalem, Israel

    Shimon Edvardson

Authors
  1. Alessia Nasca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ivano Di Meo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yakov Fellig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ann Saada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Orly Elpeleg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniele Ghezzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shimon Edvardson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Daniele Ghezzi or Shimon Edvardson.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nasca, A., Di Meo, I., Fellig, Y. et al. A novel homozygous MSTO1 mutation in Ashkenazi Jewish siblings with ataxia and myopathy. J Hum Genet 66, 835–840 (2021). https://doi.org/10.1038/s10038-020-00897-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-020-00897-4

Search

Advanced search

Quick links