SEARCH FOR MUTATIONS IN THE BETA-1 GABA(A) RECEPTOR SUBUNIT GENE IN PATIENTS WITH SCHIZOPHRENIA

As alterations in GABAergic neurotransmission have been indirectly implicated in the pathogenetics of schizophrenia, GABA(A) receptor subunit genes are plausible candidate genes for the illness. We undertook a search for sequence variations in the coding region of beta(1) subunit gene by designing intron-based primers to amplify its 9 exons. Using single strand conformation polymorphism (SSCP) analysis, we found an exon 9 variant present in 3 of 86 unrelated schizophrenic cases derived from families having at least 2 first-degree relatives with schizophrenia. Direct sequencing of the SSCP variant revealed a C-->G nucleotide transversion at codon 396 predicting a histidine to glutamine substitution in the beta(1) peptide. The predicted amino acid substitution occurs at a highly conserved site, 9 residues from a cAMP-dependent serine phosphorylation consensus sequence. All known GABA(A) beta(1) subunit genes including human, bovine, and rat, code for histidine at position 396. Although the variant cosegregated with disease in a family with 2 affected sibs, it was only transmitted to 2 of 3 affected sibs in a multiplex family, The variant was not found in an additional sample comprising 155 unrelated schizophrenics and the sequence variant was present at a low frequency (similar to 1.1%) in control groups. Although these results indicate that the sequence variant is likely to be a natural polymorphism, it is possible that the variant may be a predisposing allele in rare instances. It is also possible that the variant may change the function or regulation of the GABA(A) receptor complex and it may be of pharmacogenetic relevance. (C) 1994 Wiley-Liss, Inc.