Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans

• DOI: 10.1212/wnl.0b013e3182a841a3
• Publication Date: 2013-09-28T05:19:13Z
• Authors: L. Benjamin Hills; Amira Masri; Kotaro Konno; Wataru Kakegawa; Anh-Thu N. Lam; Elizabeth Lim-Melia; Nandini Chandy; R. Sean Hill; Jennifer N. Partlow; Muna Al-Saffar; Ramzi Nasir; Joan M. Stoler; A. James Barkovich; Masahiko Watanabe; Michisuke Yuzaki; Ganeshwaran H. Mo...
• Keywords: Cerebellar ataxia

To identify the genetic cause of a syndrome causing cerebellar ataxia and eye movement abnormalities.We identified 2 families with ataxia, abnormalities, global developmental delay. We performed analyses including single nucleotide polymorphism genotyping, linkage analysis, array comparative genomic hybridization, quantitative PCR, Sanger sequencing. obtained recordings mutant mice deficient for ortholog candidate gene, immunohistochemistry using human mouse brain specimens.All affected individuals had most notably tonic upgaze, delayed speech cognitive development. Homozygosity mapping disease locus on chromosome 4q. Within this region, homozygous deletion GRID2 exon 4 in index family compound heterozygous deletions involving second were identified. Grid2-deficient showed larger spontaneous random movements compared to wild-type mice. In developing cerebella, localized Purkinje cell dendritic spines. Brain MRI children progressive atrophy, which was more severe than that mice.Biallelic lead upgaze humans. The phenotypic resemblance similarity protein expression pattern between humans suggest conserved role synapse organization parallel fibers cells. However, atrophy seen could indicate an evolutionarily unique cerebellum.