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http://purl.uniprot.org/citations/25841024http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/25841024http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/25841024http://www.w3.org/2000/01/rdf-schema#comment"

Objectives

In a large family of Algerian origin, we aimed to identify the genetic mutation segregating with simultaneous presence of adult-onset, paucisymptomatic, slowly progressive, cerebellar ataxia in 7 adults and congenital ataxia in 1 child, and then to assess the involvement of GRID2 mutations in 144 patients with congenital cerebellar ataxia.

Methods

We used a combined approach of linkage analysis and whole-exome sequencing in one family, and a targeted gene panel sequencing approach in 144 congenital ataxias.

Results

In the large family with spinocerebellar ataxia, we identified a missense mutation (c.1966C>G/p.Leu656Val) in the GRID2 gene, in a heterozygous state in adults, and in a homozygous state in one child with congenital ataxia, compatible with a semidominant transmission pattern. In 144 patients affected with congenital ataxia, we identified 2 missense de novo GRID2 mutations in 2 children (c.1960G>A/p.Ala654Thr, c.1961C>A/p.Ala654Asp). They affect the same amino acid as the previously described Lurcher mutation in mice; the variant in the large family concerns a nearby amino acid.

Conclusions

In humans, GRID2 had only been involved in ataxia through complete loss-of-function mutations due to exon deletions. We report the first point mutations in this gene, with putative gain-of-function mechanisms, and a semidominant transmission as was observed in the Lurcher mice model. Of note, cerebellar ataxia is the core phenotype, but with variable severity ranging from very mild adult-onset to congenital-onset ataxias linked to both the heterozygous and homozygous state of the variant, and the position of the mutation."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.org/dc/terms/identifier"doi:10.1212/wnl.0000000000001524"xsd:string
http://purl.uniprot.org/citations/25841024http://purl.org/dc/terms/identifier"doi:10.1212/wnl.0000000000001524"xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Heron D."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Heron D."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Rougeot C."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Rougeot C."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Deleuze J.F."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Deleuze J.F."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Brice A."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Brice A."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Durr A."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Durr A."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Stevanin G."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Stevanin G."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Meyer V."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Meyer V."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Rodriguez D."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Rodriguez D."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Afenjar A."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Afenjar A."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Milh M."xsd:string
http://purl.uniprot.org/citations/25841024http://purl.uniprot.org/core/author"Milh M."xsd:string
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