AUTHOR=Rajan Deepa S. , Kour Sukhleen , Fortuna Tyler R. , Cousin Margot A. , Barnett Sarah S. , Niu Zhiyv , Babovic-Vuksanovic Dusica , Klee Eric W. , Kirmse Brian , Innes Micheil , Rydning Siri Lynne , Selmer Kaja K. , Vigeland Magnus Dehli , Erichsen Anne Kjersti , Nemeth Andrea H. , Millan Francisca , DeVile Catherine , Fawcett Katherine , Legendre Adrien , Sims David , Schnekenberg Ricardo Parolin , Burglen Lydie , Mercier Sandra , Bakhtiari Somayeh , Francisco-Velilla Rosario , Embarc-Buh Azman , Martinez-Salas Encarnacion , Wigby Kristen , Lenberg Jerica , Friedman Jennifer R. , Kruer Michael C. , Pandey Udai Bhan TITLE=Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in GEMIN5 JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=10 YEAR=2022 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.783762 DOI=10.3389/fcell.2022.783762 ISSN=2296-634X ABSTRACT=

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.