Coutelier Marie, Burglen Lydie, Mundwiller Emeline, Abada-Bendib Myriam, Rodriguez Diana, Chantot-Bastaraud Sandra, Rougeot Christelle, Cournelle Marie-Anne, Milh Mathieu, Toutain Annick, Bacq Delphine, Meyer Vincent, Afenjar Alexandra, Deleuze Jean-François, Brice Alexis, Héron Delphine, Stevanin Giovanni, Durr Alexandra
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.
Neurology. 2015 Apr 28;84(17):1751-9. doi: 10.1212/WNL.0000000000001524. Epub 2015 Apr 3.
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.
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.
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.
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.
在一个起源于阿尔及利亚的大家庭中，我们旨在鉴定与7名成年人出现成人起病、症状轻微、进展缓慢的小脑共济失调以及1名儿童出现先天性共济失调同时存在的遗传突变，然后评估144例先天性小脑共济失调患者中GRID2突变的情况。
我们在一个家族中采用了连锁分析和全外显子组测序相结合的方法，在144例先天性共济失调患者中采用了靶向基因panel测序方法。
在患有脊髓小脑共济失调的大家庭中，我们在GRID2基因中鉴定出一个错义突变（c.1966C>G/p.Leu656Val），在成年人中为杂合状态，在一名先天性共济失调儿童中为纯合状态，符合半显性遗传模式。在144例先天性共济失调患者中，我们在2名儿童中鉴定出2个新生的错义GRID2突变（c.1960G>A/p.Ala654Thr，c.1961C>A/p.Ala654Asp）。它们影响的氨基酸与先前在小鼠中描述的Lurcher突变相同；大家庭中的变体涉及附近的一个氨基酸。
在人类中，GRID2仅通过外显子缺失导致的功能完全丧失突变与共济失调有关。我们报告了该基因的首个点突变，具有推定的功能获得机制，以及如在Lurcher小鼠模型中观察到的半显性遗传。值得注意的是，小脑共济失调是核心表型，但严重程度各不相同，从非常轻微的成人起病到与变体的杂合和纯合状态以及突变位置相关的先天性起病共济失调。
