. 2010 Dec;1802(12):1299–1308. doi: 10.1016/j.bbadis.2009.12.006

Table 1.

Mendelian forms of hypotension and hypertension.

Disorder	Gene/locus	Age of onset	Disease mechanism	Features	References
Syndromes associated with low blood pressure
Gitelman syndrome	SLC12A3	Adolescence or adulthood	Loss-of-function mutations in the gene encoding the thiazide-sensitive Na–Cl cotransporter of the distal collecting duct causes salt wasting and activation of the renin–angiotensin–aldosterone system. Thereby maintenance of serum sodium but loss of potassium and H⁺ by augmentation of the epithelial sodium channel	Hypokalaemia with metabolic alkalosis. Low serum Mg²⁺ and low urinary Ca²⁺ levels	[103,104]
Gitelman syndrome	16q3	Adolescence or adulthood			[103,104]
Bartter syndrome				Often associated with preterm delivery. In contrast to Gitelman syndrome, normal or only mildly reduced serum Mg²⁺ and increased urinary Ca²⁺ levels
Type 1	SLC12A	Neonatal	Loss of function of the apical Na–K–2Cl cotransporter		[105]
Type 1	15q21	Neonatal	Loss of function of the apical Na–K–2Cl cotransporter		[105]
Type 2	KCNJ1	Neonatal	Mutations of the ATP-sensitive K⁺ channel ROMK affect K⁺ recycling and thereby inhibit Na⁺ reabsorption in the thick ascending limb of Henle		[106]
Type 2	11q24	Neonatal			[106]
Type 3	CLCNKB	School age	Loss-of-function mutations in the Cl⁻ channel CLCNKB in the thick ascending limb of Henle. Some of these mutations have arisen from unequal crossing over between CLCNKB and the nearby related gene CLCNKA		[107]
Type 3	1p36	School age			[107]
Type 4	BSND	Neonatal	BSND encodes Barttin which functions as a beta-subunit for CLCNKA and CLCNKB chloride channels	Associated with sensorineural deafness. inhibition of NaCl reabsorption in type IV Bartter syndrome is not restricted to the thick ascending limb of Henle	[108]
Type 4	1p32	Neonatal			[108]
Type 5	CASR	Adulthood	Mutations activating the calcium-sensing receptor CaSR which then inhibits sodium transport in the thick ascending limb of the loop of Henle	Associated with autosomal dominant hypocalcaemia (ADH)	[109]
Type 5	3q13	Adulthood		Associated with autosomal dominant hypocalcaemia (ADH)	[109]
Autosomal dominant pseudohypoaldosteronism type I	NR3C2	Neonatal	Loos/of/function mutations in the mineralocorticoid receptor impairing maximum salt absorption. The reduced activity of the endothelial sodium channel affects H⁺ and K⁺ excretion	Salt wasting with hypotension despite markedly elevated aldosterone levels; hyperkalemia and metabolic acidosis. Often asymptomatic in adulthood on usual western (high salt) diet	[110,111]
Autosomal dominant pseudohypoaldosteronism type I	4q31	Neonatal			[110,111]
Recessive pseudohypoaldosteronism type I	SCNN1A	Neonatal	Loss-of-function mutations in any of the three different subunits of the epithelial sodium channel	Salt wasting and hypotension with hyperkalemia and metabolic acidosis, despite high levels of aldosterone. Require high dose salt supplementation	[112]
	16p12
	SCNN1B
	12p13
	SCNN1G
	16p12

Syndromes associated with high blood pressure
Glucorticoid-remediable aldosteronism	CYP11B2 and CYP11B1	Second or third decade	Gene duplication due to unequal crossing over between the aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) genes. The resulting chimaeric gene encodes a protein under the regulation of ACTH with aldosterone synthase activity	Normal or elevated aldosterone levels despite suppressed plasma renin activity. Hypokalaemia and metabolic alkalosis are variable associated findings. Exogenous glucocorticoids completely suppress aldosterone secretion	[113–116]
Glucorticoid-remediable aldosteronism	8q21	Second or third decade			[113–116]
Apparent mineralocorticoid excess	HSD11B2	Childhood	Absence of the enzyme 11β-hydroxysteroid dehydrogenase allows cortisol to activate MR, resulting in hypertension mediated by increased epithelial sodium channel activity	Hypokalaemia and metabolic alkalosis accompanied by suppressed plasma renin activity and the virtual absence of circulating aldosterone	[117,118]
Apparent mineralocorticoid excess	16q22	Childhood			[117,118]
Hypertension exacerbated in pregnancy	NR3C2	Before second decade	Missense mutation, S810L, in the mineralocorticoid receptor causing normal activation by aldosterone but also activation by ligands that are normally silent or antagonistic (e.g. progesterone)	Exacerbation during pregnancy due to the increased progesterone levels	[119]
Hypertension exacerbated in pregnancy	4q31	Before second decade			[119]
Liddle syndrome	SCNN1B	Adolescence	Mutations in either the β or the γ subunit of the epithelial sodium channel delete their cytoplasmic C termini and result in increased channel activity	Associated with hypokalaemic alkalosis, suppressed plasma renin activity, and low plasma aldosterone levels	[120–122]
	12p13
	SCNN1G
	16p12
Pseudohyperaldosteronism type II (Gordon syndrome)	WNK1, 12p13	Second or third decade	WNK kinases are expressed in the distal nephron and are involved in the control of renal electrolyte homeostasis	Hyperkalaemia and low aldosterone levels. Sensitive to treatment with thiazide diuretics	[95,98]
Pseudohyperaldosteronism type II (Gordon syndrome)	WNK4, 17q21	Second or third decade			[95,98]