Partial tandem duplication of GRIA3 in a male with mental retardation

Abstract

The genetic factors underlying mental retardation (MR) are very heterogeneous. Recent studies have identified a number of genes involved in MR, several of which lie on the X-chromosome, but the current understanding of the monogenic causes of MR is far from complete. Investigation of chromosomal rearrangements in patients with MR has proven particularly informative in the search for novel genes. Using array-based comparative genomic hybridization analysis, we identified a small copy number gain at Xq25, which was undetectable by conventional G-band analysis, in a boy with unexplained MR. Further characterization revealed a partial tandem duplication of GRIA3, an alteration also present on one allele in his mother. RT-PCR analysis of lymphoblastoid cell RNA revealed remarkably reduced GRIA3 transcript levels in the patient. The mother, whose cognitive level is normal, also demonstrated remarkably reduced GRIA3 transcript levels in lymphoblastoid cells, and X-chromosome inactivation (XCI) was completely skewed in her peripheral lymphocytes. It is possible that XCI in the brain is not completely skewed and that GRIA3 expression from the normal allele may account for the mother's normal cognitive function. Taken together with previous findings of GRIA3 disruptions in the patients with MR, our study strengthens the idea that GRIA3 is a candidate gene for X-linked MR and that severely reduced GRIA3 expression results in MR.

Recurrent Rearrangements in Synaptic and Neurodevelopmental Genes and Shared Biologic Pathways in Schizophrenia, Autism, and Mental Retardation

“…A partial duplication of the GRIA3 gene, including the promoter region and the exons coding for the proximal region of GRIA3, was detected in a single case with autism. Although slightly different based on its size and the number of duplicated exons, this partial duplication is reminiscent of that recently reported in a patient with MR. 23 At the 8p23 locus, gain and loss of material were found, as well as at the 16p11 and 17q21 loci, as recently described. 22,24,25 This suggests that dosage-sensitive genes, whose expression is finely tuned, are located within these rearranged segments.…”

X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes

“…Ionotropic glutamate receptors (iGluRs) are related to learning and memory [33]. In vitro functional studies on GRIA3 missense variants have shown that mutations in functional domains of GRIA3 are associated with kinetic changes in AMPA receptor function leading to significant reduction in iGluR3 channel function which is found to be linked with moderate ID [34,35]. Previously, four missense mutations, one whole gene deletion and three duplications have been reported in GRIA3 [34-38].…”

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

“…For the GRIA gene family, there have been reports of a fusion transcript in GRIA2, a de novo interstitial deletion of chromosome 4q32 that contains the GRIA2 loci, missense mutations in the ligand binding and transmembrane domains of the GluA3 subunit (GRIA3), partial tandem duplication that reduced GRIA3 transcript levels, as well as frameshift in the GRIA3 gene ( Fig. 5; Supplemental Table S3) (Chiyonobu et al, 2007;Wu et al, 2007;Bonnet et al, 2009Bonnet et al, , 2012Poot et al, 2010;Tzschach et al, 2010;Hackmann et al, 2013;Philips et al, 2014). These data suggest that mutations within the GRIA gene family participate in a small subset of patients with intellectual disability; however, few cellular or mechanistic studies of these modifications have been reported.…”