Association of a human G-protein β3 subunit variant with hypertension

Abstract

Hypertension is a common disorder of multifactorial origin that constitutes a major risk factor for cardiovascular events such as stroke and myocardial infarction. Previous studies demonstrated an enhanced signal transduction via pertussis toxin-sensitive G proteins in lymphoblasts and fibroblasts from selected patients with essential hypertension. We have detected a novel polymorphism (C825T) in exon 10 of the gene encoding the beta3 subunit of heterotrimeric G proteins (GNB3). The T allele is associated with the occurrence of a splice variant, GNB3-s (encoding G beta3-s), in which the nucleotides 498-620 of exon 9 are deleted. This in-frame deletion causes the loss of 41 amino acids and one WD repeat domain of the G beta subunit. By western-blot analysis, G beta3-s appears to be predominantly expressed in cells from individuals carrying the T allele. Significant enhancement of stimulated GTPgammaS binding to Sf9 insect cells expressing G beta3-s together with G alpha(i)2 and G gamma5 indicates that this splice variant is biologically active. Genotype analysis of 427 normotensive and 426 hypertensive subjects suggests a significant association of the T allele with essential hypertension.

Interactions between five candidate genes and antihypertensive drug therapy on blood pressure

“…12 Genotype Genomic DNA was isolated from peripheral blood according to standard procedures. The genotyping procedure of ADD1 G460W, 13 ACE I/D, 5 AGT M235T, 14 GNB3 825C/T, 15 and AGTR1 1166A/C 16 was previously described.…”

Interaction between GNB3 C825T and ACE I/D polymorphisms in essential hypertension in Koreans

“…Variations within genes encoding for G proteins and mutations altering the expression of these proteins may cause or contribute to many different diseases including CVD. 21 Siffert et al 21 identified a single-nucleotide polymorphism, C825T, at nucleotide position 825 in exon 10 of the gene encoding the G protein b3-subunit (GNB3). The 825T allele is associated with a splice variant (Gb3s), in which the nucleotides 498-620 of exon 9 are deleted, causing loss of 41 amino acids and one conserved Trp-Asp (WD) repeat domain of the Gb3-subunit.…”

“…Additionally, GNB3 affects the activity of sodium hydrogen exchanger (NHE), which regulated an electroneutral exchange of extracellular Na þ for intracellular H þ , contributing to pH and sodium homeostasis. 22 In 1998, Siffert et al 21 reported that the hypertensive patients showed increased NHE activity and the activity of G-protein complex sensitive to pertussis toxin (G i ) in these patients was increased. G i protein formed of mutated subunit variants (b3s, b i 2 and b5) shows the increased NHE activity.…”

“…The recent reports indicate that the presence of GNB3 825T carriers associated with the increased activity of NHE in hypertensive subjects. 21,23 To date, association studies have shown that the GNB3 825T allele is significantly associated with EH in Africans 24 and Caucasians, 25 and it is also associated with variations in BP. However, the effects of the 825T allele on variations in EH and BP among Asian populations have presented conflicting results.…”

Diminished GABAA Receptor-Binding Capacity and a DNA Base Substitution in a Patient with Treatment-Resistant Depression and Anxiety

“…Therefore, this polymorphism is probably without functional significance. However it is possible that this polymorphism could be related to an altered GABA A receptor function, since it has been demonstrated that alternative splicing resulting in a mutant version of the protein may be caused by nucleotide changes outside of the splice donor or acceptor sites (Siffert et al, 1998).…”