GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia

Neurology. 2015 Apr 28;84(17):1751-9. doi: 10.1212/WNL.0000000000001524. Epub 2015 Apr 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Algeria
  • Cerebellar Ataxia / congenital
  • Cerebellar Ataxia / genetics*
  • Child
  • Child, Preschool
  • Exome
  • Female
  • Genetic Linkage
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Pedigree
  • Point Mutation / genetics*
  • Receptors, Glutamate / genetics*
  • Sequence Analysis, DNA


  • Receptors, Glutamate
  • glutamate receptor delta 2