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

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 molecula...

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Detalles Bibliográficos
Autores: 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, Martínez-Salas, Encarnación, Wigby, Kristen, Lenberg, Jerica, Friedman, Jennifer R., Kruer, Michael C., Pandey, Udai Bhan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/367868
Acceso en línea:http://hdl.handle.net/10261/367868
Access Level:acceso abierto
Palabra clave:Gemin5
ataxia
cell death
cerebellar atrophy
development
developmental delay
neurodegeneration.
Descripción
Sumario: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.

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