Mutations in the Na-Cl Cotransporter Reduce Blood Pressure in Humans

Abstract

Abstract-The relationship between salt homeostasis and blood pressure has remained difficult to establish from epidemiological studies of the general population. Recently, mendelian forms of hypertension have demonstrated that mutations that increase renal salt balance lead to higher blood pressure, suggesting that mutations that decrease the net salt balance might have the converse effect. Gitelman's syndrome, caused by loss of function mutations in the Na-Cl cotransporter of the distal convoluted tubule (NCCT), features inherited hypokalemic alkalosis with so-called "normal" blood pressure. We hypothesized that the mild salt wasting of Gitelman's syndrome results in reduced blood pressure and protection from hypertension. We have formally addressed this question through the study of 199 members of a large Amish kindred with Gitelman's syndrome. Through genetic testing, family members were identified as inheriting 0 (nϭ60), 1 (nϭ113), or 2 (nϭ26) mutations in NCCT, permitting an unbiased assessment of the clinical consequences of inheriting these mutations by comparison of the phenotypes of relatives with contrasting genotypes. The results demonstrate high penetrance of hypokalemic alkalosis, hypomagnesemia, and hypocalciuria in patients inheriting 2 mutant NCCT alleles. In addition, the NCCT genotype was a significant predictor of blood pressure, with homozygous mutant family members having significantly lower age-and gender-adjusted systolic and diastolic blood pressures than those of their wild-type relatives. Moreover, both homozygote and heterozygote subjects had significantly higher 24-hour urinary Na ϩ than did wild-type subjects, reflecting a self-selected higher salt intake. Finally, heterozygous children, but not adults, had significantly lower blood pressures than those of the wild-type relatives. These findings provide formal demonstration that inherited mutations that impair renal salt handling lower blood pressure in humans.

A High Prevalence of Gitelman's Syndrome Mutations in Japanese

“…The frequencies of the 180K, 569V, and 849H alleles were unexpectedly high: 1.51, 0.38, and 1.27%, respectively. Blood pressure levels of heterozygous subjects with the GS mutations were not significantly different from those of wild-type subjects, which agreed with the study by Cruz et al (2). However, we could not re-examine the observation by Cruz et al that younger (<18 years) subjects heterozygous for a GS mutation had lower blood pressure levels, since our study population consisted of subjects more than 30 years old.…”

“…However, we could not re-examine the observation by Cruz et al that younger (<18 years) subjects heterozygous for a GS mutation had lower blood pressure levels, since our study population consisted of subjects more than 30 years old. Although heterozygous GS mutations do not influence blood pressure levels in Japanese, homozygous GS mutations are expected to reduce blood pressure levels, as reported by Cruz et al (2) and as suggested by our observation that a subject with possible compound heterozygous mutations (180K and 849H) had a low blood pressure level. If we accept the 8 GS mutations reported in Japanese (6-9), the combined frequency of these mutations would be (56 14 1 Values are expressed as mean (SEM).…”

“…The clinical features of GS resemble the effects of thiazide administration, and reduced salt reabsorption in GS might be associated with resistance to hypertension. Indeed, using a large Amish kindred with GS, Cruz et al (2) reported that homozygous mutant and younger (<18 years) heterozygous mutant family members had lower blood pressure levels than those of their wild-type relatives. They also reported that both homozygote and heterozygote senting the general population in Japan.…”

Rare independent mutations in renal salt handling genes contribute to blood pressure variation

“…We have shown that the carrier state for rare functional mutations in NCCT, NKCC2 and ROMK reduce blood pressure in FHS participants. Each of these genes governs renal salt handling, and homozygous loss of function mutations in them lower blood pressure by reducing salt reabsorption; heterozygous mutations in NCCT have also been shown to increase renal salt loss 29 .…”

Genetics of arterial hypertension and hypotension

“…Heterozygous carriers of these mutations are normotensive but do actually consume more salt, again underscoring the tight interaction of genetic and environmental factors to blood pressure regulation. While homozygous carriers of Gitelman's or Bartter's mutations suffer from severe disorders, there is speculation that heterozygotes or carriers of other mutations that cause only mild inhibition of such transporters are protected against hypertension (Cruz et al 2001). In addition to this considerable number of loss-offunction mutations in these ion transport proteins, a gain-offunction mutation in CLCNKB has been reported that causes a conservative amino acid substitution (T481S; Fig.…”