Characterization of the Human Glutamate Receptor Subunit 3 Gene (GRIA3), a Candidate for Bipolar Disorder and Nonspecific X-Linked Mental Retardation

Abstract

The X-chromosome breakpoint in a female patient with a balanced translocation t(X;12)(q24;q15), bipolar affective disorder and mental retardation was mapped within the glutamate receptor 3 (GRIA3) gene by fluorescence in situ hybridization. The GRIA3 cDNA of 5894 bp was cloned, and the gene structure and pattern of expression were determined. The most abundant GRIA3 transcript is composed of 17 exons. An additional 5 exons (2a, 2b, 5a, 5b, and 5c) from the 5′ end of the GRIA3 open reading frame were identified by EST analysis (ESTs AI379066 and AA947914). Two new polymorphic microsatellite repeats, (TC)n=12–26 and (AC)n=15–19, were identified within GRIA3 5′ and 3′UTRs. No mutations were detected in families segregating disorders mapping across GRIA3, one with X-linked bipolar affective disorder (BP) and one with a nonspecific X-linked mental retardation (MRX27). To assess the possibility of the involvement of the GRIA3 gene in familial cases of complex BP, a large set of 373 individuals from 40 pedigrees segregating BP were genotyped using closely linked (DXS1001) and intragenic (DXS1212 and GRIA3 3′ UTR (AC)n)) GRIA3 STR markers. No evidence of linkage was found by parametric Lod score analysis (the highest Lod score was 0.3 at DXS1212, using the dominant transmission model) or by affected sib-pair analysis.