@article{a2c18682938d4238951bf4ddeedcedf9,
title = "Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in GEMIN5",
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.",
keywords = "Gemin5, ataxia, cell death, cerebellar atrophy, development, developmental delay, neurodegeneration",
author = "Rajan, {Deepa S.} and Sukhleen Kour and Fortuna, {Tyler R.} and Cousin, {Margot A.} and Barnett, {Sarah S.} and Zhiyv Niu and Dusica Babovic-Vuksanovic and Klee, {Eric W.} and Brian Kirmse and Micheil Innes and Rydning, {Siri Lynne} and Selmer, {Kaja K.} and Vigeland, {Magnus Dehli} and Erichsen, {Anne Kjersti} and Nemeth, {Andrea H.} and Francisca Millan and Catherine DeVile and Katherine Fawcett and Adrien Legendre and David Sims and Schnekenberg, {Ricardo Parolin} and Lydie Burglen and Sandra Mercier and Somayeh Bakhtiari and Encarnacion Martinez-Salas and Kristen Wigby and Jerica Lenberg and Friedman, {Jennifer R.} and Kruer, {Michael C.} and Pandey, {Udai Bhan}",
note = "Funding Information: UP and DR are thankful to the Children{\textquoteright}s Neuroscience Institute, Children{\textquoteright}s Hospital of Pittsburgh, for providing a pilot grant funding. Funding Information: The C57BL/6NTac-Gemin5/H mice and phenotypes were generated at the MRC Harwell Institute. The knockout mouse generation protocol has been approved as per MRC Harwell Institute guidelines. The MRC Harwell Institute generated the mice as part of the International Mouse Phenotyping Consortium (IMPC) and has received funding from the National Institutes for Health for generating and/or phenotyping (5UM1HG006348-08) the C57BL/6NTac-Gemin5/H mice. The research reported in this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding and associated primary phenotypic information may be found at www.mousephenotype.org . em1(IMPC)H em1(IMPC)H Publisher Copyright: Copyright {\textcopyright} 2022 Rajan, Kour, Fortuna, Cousin, Barnett, Niu, Babovic-Vuksanovic, Klee, Kirmse, Innes, Rydning, Selmer, Vigeland, Erichsen, Nemeth, Millan, DeVile, Fawcett, Legendre, Sims, Schnekenberg, Burglen, Mercier, Bakhtiari, Martinez-Salas, Wigby, Lenberg, Friedman, Kruer and Pandey.",
year = "2022",
month = feb,
day = "28",
doi = "10.3389/fcell.2022.783762",
language = "English (US)",
volume = "10",
journal = "Frontiers in Cell and Developmental Biology",
issn = "2296-634X",
publisher = "Frontiers Media S. A.",
}