Two point mutations within the adducin genes are involved in blood pressure variation.

Abstract

The Milan hypertensive strain of rats (MHS) develops a genetic form of renal hypertension that, when compared to its normotensive control (MNS), shows renal dysfunction similar to that of a subset of human patients with primary hypertension. MHS and MNS were shown to be homozygous by multilocus miisatellite analysis and monolocus microsatellite markers. We show here that one point mutation in each of two genes coding for the membrane skeleton protein adducin is associated with blood pressure in the Milan strain of rats. Adducin is a heterodimer formed by a and 13 subunits that promotes the assembly of actin with spectrin. MHS and MNS differ, respectively, by the amino acids Y and F at position 316 of the a subunit. In the ,&adducin locus, MRS is always homozygous for R at position 529 while in MNS either R or Q occurs in that position. The R/Q heterozygotes showed lower blood pressure than any of the homozygotes. In vitro phosphorylation studies suggest that both of these amino acid substitutions occur within protein kinase recognition sites. Analysis of an F2 generation demonstrated that Y alleles segregated with a significant increment in blood pressure. This effect is modulated by the presence of the R allele of the 1 subunit. Taken together, these dings strongly support a role for adducin polymorphisms in causing variation of blood pressure in the Milan strain of rats.

Antihypertensive therapy, the α-adducin polymorphism, and cardiovascular disease in high-risk hypertensive persons: the Genetics of Hypertension-Associated Treatment Study

“…26 Several studies have addressed the question of whether carriers of the Trp allele of the a-adducin gene possibly contribute to the pathogenesis of essential hypertension. 7,12,[26][27][28][29][30][31][32] The overall evidence from these experimental and clinical studies indicates that Trp allele carriers have an increased risk of hypertension attributable to an innate stimulation of the sodium pump and enhanced renal tubular sodium reabsorption. 7,[33][34][35][36][37] However, most studies in humans suggest that mutation of the a-adducin gene on its own is insufficient to cause hypertension.…”

Role of the Gly460Trp polymorphism of the α-adducin gene in primary hypertension in Scandinavians

“…[5][6][7][8] Genetic differences in renal tubular salt reabsorption could thus contribute to the development of hypertension. [9][10][11][12][13][14] Cross-immunisation of cytoskeleton proteins between MHS and the normotensive rat strain (MNS) revealed immunochemical differences in an ␣/␤ heterodimeric protein called adducin. 15 Adducin is thought to interact with the actin cytoskeleton and could thereby be important for cell signalling.…”

“…16,17 Two mutations in the ␣-adducin and the ␤-adducin genes could explain up to 50% of the differ-which the frequency of the Trp460 allele was significantly lower in hypertensive patients than in normotensive controls (17.0% vs 21 ence in blood pressure between the MHS and the MNS. 9 Transfection studies with cDNA from the MHS showed altered ability of adducin to interact with actin and increased maximum velocity of the sodium-potassium pump. 18 In humans, polymorphic markers flanking the ␣-adducin gene have been shown to be associated with primary hypertension in Italians 19 and linkage has been demonstrated between the ␣-adducin locus and primary hypertension in French families.…”

Association of the α-adducin polymorphism with blood pressure and risk of myocardial infarction

“…1 The Gly460 → Trp polymorphism of an ␣-adducin subunit is associated with hypertension in French and Italian populations. 2 Blood pressure responses to acute salt-sensitivity tests and to chronic diuretic therapy were more pronounced in heterozygotes than in wild-type homozygotes.…”