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

Citation
H. Coon et al., SEARCH FOR MUTATIONS IN THE BETA-1 GABA(A) RECEPTOR SUBUNIT GENE IN PATIENTS WITH SCHIZOPHRENIA, American journal of medical genetics, 54(1), 1994, pp. 12-20
Citations number
64
Categorie Soggetti
Genetics & Heredity
ISSN journal
01487299
Volume
54
Issue
1
Year of publication
1994
Pages
12 - 20
Database
ISI
SICI code
0148-7299(1994)54:1<12:SFMITB>2.0.ZU;2-A
Abstract
As alterations in GABAergic neurotransmission have been indirectly imp licated in the pathogenetics of schizophrenia, GABA(A) receptor subuni t 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 e xon 9 variant present in 3 of 86 unrelated schizophrenic cases derived from families having at least 2 first-degree relatives with schizophr enia. Direct sequencing of the SSCP variant revealed a C-->G nucleotid e transversion at codon 396 predicting a histidine to glutamine substi tution in the beta(1) peptide. The predicted amino acid substitution o ccurs at a highly conserved site, 9 residues from a cAMP-dependent ser ine phosphorylation consensus sequence. All known GABA(A) beta(1) subu nit genes including human, bovine, and rat, code for histidine at posi tion 396. Although the variant cosegregated with disease in a family w ith 2 affected sibs, it was only transmitted to 2 of 3 affected sibs i n a multiplex family, The variant was not found in an additional sampl e comprising 155 unrelated schizophrenics and the sequence variant was present at a low frequency (similar to 1.1%) in control groups. Altho ugh these results indicate that the sequence variant is likely to be a natural polymorphism, it is possible that the variant may be a predis posing 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.