Frontiers in Cell and Developmental Biology (Feb 2022)

Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in GEMIN5

  • Deepa S. Rajan,
  • Sukhleen Kour,
  • Tyler R. Fortuna,
  • Margot A. Cousin,
  • Margot A. Cousin,
  • Sarah S. Barnett,
  • Zhiyv Niu,
  • Zhiyv Niu,
  • Dusica Babovic-Vuksanovic,
  • Dusica Babovic-Vuksanovic,
  • Dusica Babovic-Vuksanovic,
  • Eric W. Klee,
  • Eric W. Klee,
  • Eric W. Klee,
  • Eric W. Klee,
  • Brian Kirmse,
  • Micheil Innes,
  • Siri Lynne Rydning,
  • Kaja K. Selmer,
  • Magnus Dehli Vigeland,
  • Anne Kjersti Erichsen,
  • Andrea H. Nemeth,
  • Francisca Millan,
  • Catherine DeVile,
  • Katherine Fawcett,
  • Katherine Fawcett,
  • Adrien Legendre,
  • David Sims,
  • Ricardo Parolin Schnekenberg,
  • Lydie Burglen,
  • Lydie Burglen,
  • Sandra Mercier,
  • Sandra Mercier,
  • Somayeh Bakhtiari,
  • Somayeh Bakhtiari,
  • Rosario Francisco-Velilla,
  • Azman Embarc-Buh,
  • Encarnacion Martinez-Salas,
  • Kristen Wigby,
  • Kristen Wigby,
  • Jerica Lenberg,
  • Jennifer R. Friedman,
  • Jennifer R. Friedman,
  • Jennifer R. Friedman,
  • Michael C. Kruer,
  • Michael C. Kruer,
  • Udai Bhan Pandey

DOI
https://doi.org/10.3389/fcell.2022.783762
Journal volume & issue
Vol. 10

Abstract

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The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets. Here, we describe the identification of biallelic variants in the GEMIN5 gene among seven unrelated families with nine affected individuals presenting with spastic ataxia and cerebellar atrophy. GEMIN5, an RNA-binding protein, has been shown to regulate transcription and translation machinery. GEMIN5 is a component of small nuclear ribonucleoprotein (snRNP) complexes and helps in the assembly of the spliceosome complexes. We found that biallelic GEMIN5 variants cause structural abnormalities in the encoded protein and reduce expression of snRNP complex proteins in patient cells compared with unaffected controls. Finally, knocking out endogenous Gemin5 in mice caused early embryonic lethality, suggesting that Gemin5 expression is crucial for normal development. Our work further expands on the phenotypic spectrum associated with GEMIN5-related disease and implicates the role of GEMIN5 among patients with spastic ataxia, cerebellar atrophy, and motor predominant developmental delay.

Keywords