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
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.