Search for mutations in the β1 GABAA receptor subunit gene in patients with schizophrenia

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Abstract
As alterations in GABAergic neurotransmission have been indirectly implicated in the pathogenetics of schizophrenia, GABAA receptor subunit genes are plausible candidate genes for the illness. We undertook a search for sequence variations in the coding region of β1 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 β1 peptide. The predicted amino acid substitution occurs at a highly conserved site, 9 residues from a cAMP‐dependent serine phosphorylation consensus sequence. All known GABAA β1 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 (∼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 GABAA receptor complex and it may be of pharmacogenetic relevance.