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

Abstract

Biallelic deletions of GRID2 lead to a syndrome of cerebellar ataxia and tonic upgaze in humans. The phenotypic resemblance and similarity in protein expression pattern between humans and mice suggest a conserved role for GRID2 in the synapse organization between parallel fibers and Purkinje cells. However, the progressive and severe cerebellar atrophy seen in the affected individuals could indicate an evolutionarily unique role for GRID2 in the human cerebellum.

Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion

“…Similar to other retina-associated genes, low Grid2 mRNA expression was found at early postnatal stages, followed by an increase during development, and reaching a steady state around adulthood. In addition, GRID2 immunostaining was shown both in human and murine retina, localizing to photoreceptor inner segments, The red bars represent a homozygous deletion of exon 2, found in ho15J mice, in the patients described by Hills et al 5 as a compound heterozygous deletion, and our proband. The blue bars represent a homozygous deletion removing both exons 3 and 4, as described in ho8/13J and tpr mice and the patients reported by Utine et al 4 The human deletion of exon 1 is a heterozygous deletion, reported by Maier et al Utine, 2013 This study the outer plexiform layer, and the ganglion cell layer.…”

“…A summary of the bioinformatics findings is given in Table 1; visualization of microhomology can be found in Supplementary Figure S1 online. Based on the results of this extensive analysis, the studied GRID2 deletions with microhomology may be caused by nonhomologous end-joining (<5-bp microhomology) or a replicative-based repair mechanism, favoring the latter because an information scar, typical of nonhomologous end-joining, was not present at the junction for our deletion and was not reported for the deletions described by Hills et al 5 The deletion without microhomology is more likely to be caused by nonhomologous end-joining. The presence of sequence motifs can result in genomic instability and the formation of a deletion.…”

“…24 Involvement of GRID2 mutations in human disease has been reported only recently, when our study was in a final stage. Utine et al 4 reported a homozygous deletion of exons 3 and 4 in a consanguineous Turkish family with ARCA and cerebellar atrophy, whereas Hills et al 5 described two additional biallelic GRID2 deletions of exon 2 (compound heterozygous) and exon 4 (homozygous) associated with ARCA and eye movements, mainly tonic upgaze. Maier et al 6 reported a heterozygous deletion of exon 1 and the upstream region of GRID2 in a 24-year-old man with spastic paraplegia, ataxia, frontotemporal dementia, and lower motor neuron involvement.…”

“…The recent study by Hills et al 5 demonstrated conservation of this selective expression in the human cerebellum. As a first step toward explaining the RD phenotype observed here, we performed expression analysis in human complementary DNA of adult and fetal cerebellum, adult cerebral cortex, adult retina, and adult retinal pigment epithelium, Retinal counterstaining was performed with 4′,6-diamidino-2-phenylindole (DAPI) (blue).…”

“…To assess the underlying mechanism of the four characterized GRID2 deletions found in our proband and in the ARCA patients reported by Hills et al, 5 a bioinformatics analysis 21 was performed on both breakpoint regions of these deletions. A summary of the bioinformatics findings is given in Table 1; visualization of microhomology can be found in Supplementary Figure S1 online.…”