GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia.
Neurology. 2015-04-03; 84(17): 1751-1759
DOI: 10.1212/WNL.0000000000001524
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1. Neurology. 2015 Apr 28;84(17):1751-9. doi: 10.1212/WNL.0000000000001524. Epub
2015 Apr 3.
GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia.
Coutelier M(1), Burglen L(1), Mundwiller E(1), Abada-Bendib M(1), Rodriguez D(1),
Chantot-Bastaraud S(1), Rougeot C(1), Cournelle MA(1), Milh M(1), Toutain A(1),
Bacq D(1), Meyer V(1), Afenjar A(1), Deleuze JF(1), Brice A(1), Héron D(1),
Stevanin G(1), Durr A(2).
Author information:
(1)From Institut du Cerveau et de la Moelle épinière (M.C., A.B., G.S., A.D.),
ICM, Paris; CNRS (M.C., A.B., G.S., A.D.), UMR 7225, Paris; Sorbonne Universités
(M.C., A.B., G.S., A.D.), UPMC Univ Paris 06, UMRS_1127, Paris; INSERM (M.C.,
E.M., A.B., G.S., A.D.), U 1127, Paris, France; Laboratory of Human Molecular
Genetics (M.C.), de Duve Institute, Université catholique de Louvain, Brussels,
Belgium; Laboratoire de Neurogénétique (M.C., G.S.), Ecole Pratique des Hautes
Etudes, ICM, GHU Pitié-Salpêtrière, Paris; Centre de Référence Malformations et
Maladies Congénitales du Cervelet (L.B., D.R., S.C.-B., C.R., A.A.),
Paris-Lyon-Lille; INSERM U1141 (L.B., D.R.), Paris; APHP (L.B., S.C.-B.),
Armand-Trousseau Hospital, Department of Genetics, Paris, France; Service de
Neurologie (M.A.-B.), CHU Bab el Oued, Alger, Algeria; APHP (D.R., A.A.),
Armand-Trousseau Hospital, Department of Neuropediatrics, UPMC Univ Paris 06;
Hospices Civils de Lyon (C.R.), HFME, Service de Neuropédiatrie, Bron; Centre
Hospitalier du Pays d’Aix (M.-A.C.), Service de Pédiatrie, Aix en Provence; APHM
(M.M.), Service de neurologie pédiatrique, Hôpital de la Timone, Marseille;
Service de Génétique (A.T.), Hôpital Bretonneau, Centre Hospitalier
Universitaire, Tours; Centre National de Génotypage (D.B., V.M., J.-F.D.),
Institut de Génomique, CEA, Evry; APHP (A.B., D.H., A.D.), Department of Genetics
and Cytogenetics, Groupe Hospitalier Pitié-Salpêtrière, Paris; Centre de
Référence Déficiences Intellectuelles de causes rares (D.H.), Paris; and Groupe
de Recherche Clinique déficiences intellectuelles (D.H.), UPMC Univ Paris 06,
France.
(2)From Institut du Cerveau et de la Moelle épinière (M.C., A.B., G.S., A.D.),
ICM, Paris; CNRS (M.C., A.B., G.S., A.D.), UMR 7225, Paris; Sorbonne Universités
(M.C., A.B., G.S., A.D.), UPMC Univ Paris 06, UMRS_1127, Paris; INSERM (M.C.,
E.M., A.B., G.S., A.D.), U 1127, Paris, France; Laboratory of Human Molecular
Genetics (M.C.), de Duve Institute, Université catholique de Louvain, Brussels,
Belgium; Laboratoire de Neurogénétique (M.C., G.S.), Ecole Pratique des Hautes
Etudes, ICM, GHU Pitié-Salpêtrière, Paris; Centre de Référence Malformations et
Maladies Congénitales du Cervelet (L.B., D.R., S.C.-B., C.R., A.A.),
Paris-Lyon-Lille; INSERM U1141 (L.B., D.R.), Paris; APHP (L.B., S.C.-B.),
Armand-Trousseau Hospital, Department of Genetics, Paris, France; Service de
Neurologie (M.A.-B.), CHU Bab el Oued, Alger, Algeria; APHP (D.R., A.A.),
Armand-Trousseau Hospital, Department of Neuropediatrics, UPMC Univ Paris 06;
Hospices Civils de Lyon (C.R.), HFME, Service de Neuropédiatrie, Bron; Centre
Hospitalier du Pays d’Aix (M.-A.C.), Service de Pédiatrie, Aix en Provence; APHM
(M.M.), Service de neurologie pédiatrique, Hôpital de la Timone, Marseille;
Service de Génétique (A.T.), Hôpital Bretonneau, Centre Hospitalier
Universitaire, Tours; Centre National de Génotypage (D.B., V.M., J.-F.D.),
Institut de Génomique, CEA, Evry; APHP (A.B., D.H., A.D.), Department of Genetics
and Cytogenetics, Groupe Hospitalier Pitié-Salpêtrière, Paris; Centre de
Référence Déficiences Intellectuelles de causes rares (D.H.), Paris; and Groupe
de Recherche Clinique déficiences intellectuelles (D.H.), UPMC Univ Paris 06,
France. .
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.
© 2015 American Academy of Neurology.
DOI: 10.1212/WNL.0000000000001524
PMID: 25841024 [Indexed for MEDLINE]