Related Experiment Videos
Association of a human G-protein beta3 subunit variant with hypertension
W Siffert1, D Rosskopf, G Siffert
1Institut für Pharmakologie, Universitätsklinikum Essen, Germany. winfried.siffert@uni-essen.de
Insights
A novel gene variant (T allele) in the GNB3 gene is linked to essential hypertension. This variant leads to a splice variant (GNB3-s) that enhances cellular signaling, potentially increasing cardiovascular risk.
Area of Science:
- Molecular Biology
- Genetics
- Cardiovascular Disease
Background:
- Hypertension is a major risk factor for cardiovascular events like stroke and myocardial infarction.
- Previous research indicated enhanced G protein signaling in essential hypertension patients.
Purpose of the Study:
- To identify genetic factors contributing to essential hypertension.
- To investigate the functional significance of a novel GNB3 gene polymorphism.
Main Methods:
- Identified a C825T polymorphism in the GNB3 gene.
- Characterized the GNB3-s splice variant using western-blot analysis.
- Assessed G protein signaling enhancement via GTPgammaS binding assays.
- Conducted genotype analysis in hypertensive and normotensive subjects.
Main Results:
- The T allele of the C825T polymorphism is associated with a GNB3 splice variant (GNB3-s).
- GNB3-s results in the deletion of 41 amino acids and a WD repeat domain.
- GNB3-s is predominantly expressed in individuals with the T allele.
- The GNB3-s variant shows enhanced biological activity in cellular signaling.
- A significant association was found between the T allele and essential hypertension.
Conclusions:
- The novel GNB3 C825T polymorphism and its associated splice variant (GNB3-s) are linked to essential hypertension.
- This genetic variation may contribute to increased cardiovascular risk through enhanced G protein signaling.
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.