MENDELIAN MONOGENIC FORMS OF HYPERTENSION

An interesting feature of monogenic forms of hypertension disorders is that most of them affect either electrolyte transport in the renal tubule or the synthesis and/or activity of mineralocorticoid hormones. In all monogenic hypertensive disorders thus far, the final common pathway to hypertension appears to be increased sodium reabsorption and volume expansion. Monogenic hypertension, however, is rare and all of the known forms together account for less than 1 percent of human hypertension.

Glucocorticoid remediable aldosteronism

CYP11B1/CYP11B2 genes encoding steroid 11β- hydroxylase/aldosterone synthase are located on chromosome 8p (Lifton,et al., 1992).Glucocorticoid-remediable aldosteronism is inherited as an autosomal dominant trait caused by gene duplication derived from a meiotic mismatch and unequal crossing between the genes encoding for aldosterone synthase and 11b-hydroxylase. This causes aldosterone secretion to be regulated by adrenocorticotropic hormone. As a result, high amounts of aldosterone will be secreted leading to increased salt and water re-absorption and rise in blood pressure(Lifton,et al., 1992).

Pseudoaldosteronism (Liddle’s Syndrome)

SCNN1Band SCNN1G genes encoding for β- and γ - subunits of epithelial Na⁺ channel respectively; on chromosome 16p (Melander,et al., 1998).Liddle’s Syndrome is an autosomal dominant form of monogenic hypertension that results from mutations in the amiloride-sensitive ENaC. Several mutations that result in the elimination of 45 to 75 amino acids from the cytoplasmic carboxyl terminus of β- or γ-subunits of the channel have been reported. Mutations that increase ENaC activity, in turn, cause excessive distal and collecting tubule sodium reabsorption and hypertension (Garovic,et al., 2006).

Syndrome of apparent mineralocorticoid excess

HSD11B2gene encoding 11β-hydroxysteroid dehydrogenase 2 is located on chromosome 16q (Stewart,et al., 1996).Apparent mineralocorticoid excess is an autosomal recessive form of monogenic hypertension that results from a mutation in the renal-specific isoform of the 11β-hydroxysteroid dehydrogenase gene. This enzyme normally converts cortisol to the inactive metabolite cortisone and "protects" the mineralocorticoidreceptor (MR) from being activated by cortisol. This is important because the renal epithelial MR receptor in the distal and collecting tubules has a similar affinity for aldosterone and cortisol, while cortisol concentrations are normally much higher than aldosterone. Deficiency of 11β-hydroxysteroid dehydrogenase allows the tubular MR to be occupied and activated by cortisol, causing sodium retention and volume expansion, low renin, low aldosterone, and a form of hypertension that is salt sensitive(Mune, et al., 1995).

Mineralocorticoid receptor (MR) activating mutation

NR3C2gene encoding mineralocorticoid receptor; on chromosome 4q (Geller,et al., 2000).This monogenic disorder is caused by a substitution of leucine for serine at codon 810 of the MR. This mutation alters the shape and the specificity of the MR and eliminates the usual requirement for the 21-hydroxyl group of aldosterone to interact with the MR. All steroids, including progesterone, that display antagonist properties when bound to the wild-type MR are able to activate the mutant receptor (Geller,et al., 2000).

Pseudohypoaldosteronism type II (Gordon’s syndrome)

Pseudohypoaldosteronism type II is an autosomal dominant disease characterized by severe hypertension, hyperkalemia and sensitivity to thiazide diuretics (Yang,et al., 2003). The disorder is caused by mutations in two genes encoding the serine/threonine protein kinases: WNK1 and WNK4 (Wilson,et al., 2001). The phenotypes of excessive salt retention and hypertension are caused by loss of normal inhibition or to constitutive activation of the renal tubular NaClcotransporter by mutant WNK1 or WNK4 genes in pseudohypoaldosteronism type II patients (Garovic,et al., 2006).

TABLE : Causative Mutation of Mendelian Form of Hypertension

ENaC:Epithelial Na⁺ channel          MR:Mineralocorticoid receptor            BP: Blood pressure