The identification of variant (allelic) genes that contribute to the development of hypertension is complicated by the fact that the two phenotypes that determine blood pressure, cardiac output and total peripheral resistance, are controlled by intermediary phenotypes, including the autonomic nervous system, vasopressor/vasodepressor hormones, the structure of the cardiovascular system, body fluid volume and renal function, and many others. Furthermore, this intermediary phenotypes are also controlled by complex mechanisms including blood pressure itself [26].
Mutations in at least 10 genes have been shown to raise or lower blood pressure through a common pathway by increasing or decreasing salt and water reabsorption by the nephron [27, 14]. The mutations responsible for 3 rare forms of mendelian hypertensive syndromes – glucocorticoid-remediable aldosteronism (GRA), Liddle’s syndrome and apparent mineralocorticoid excess – have been identified, whereas in 2 others, Gordon’s syndrome and autosomal dominant hypertension with brachydactyly, the genes are not yet identified but have been mapped to chromosomes 1, 17 and 12p.
Glucocorticoid-remediable aldosteronism (GRA) is an autosomal dominant form of moderate-to-severe hypertension associated with both an excess of cerebral haemorrhage and Celtic ancestry [28]. The hypertension is caused by excessive secretion of aldosterone, where aldosterone secretion is regulated by corticotrophin (ACTH) rather than by angiotensin II [29]. Kindreds with GRA demonstrate a novel gene on chromosome 8 that represents duplication arising from unequal crossover between the aldosterone synthase and 11 β-hydroxylase genes, such that the regulatory sequences of 11 β-hydroxylase are fused with coding sequences of aldosterone synthase [29]. Aldosterone synthase gene expression and enzymatic activity are therefore brought under the control of ACTH. The chimeric gene results in ectopic production of aldosterone with hypertension due to increased salt and water retention [29].
Identification of the mechanism of this rare Mendelian hypertension explains the reduction in blood pressure in response to administration of physiological doses of glucocorticoids which suppress ACTH secretion and thereby suppress expression of the mutant gene. It is now possible to define these individuals using a simple genetic test rather than extensive biochemical phenotyping. This is the first example of such an approach in clinical practice to identify hypertensive individuals who should receive glucocorticoids as antihypertensive therapy.
The syndrome of apparent mineralocorticoid excess is an autosomal recessive disorder that produces moderate-to-severe hypertension of early onset with very low levels of aldosterone [30]. The hypertension is caused by stimulation of the mineralocorticoid receptor by cortisol, which circulates at levels that are orders of magnitude higher than those of aldosterone. Since cortisol has equal affinity for the mineralocorticoid receptor there is, in normal circumstances, a protective mechanism which operates in the distal convoluted tubule whereby the enzyme 11 β-hydroxysteroid dehydrogenase type 2 metabolises cortisol to cortisone. Cortisone is incapable of stimulating the mineralocorticoid receptor and this prevents cortisol from acting at the mineralocorticoid receptor, resulting in selective activation by aldosterone [30]. Mutations in the gene coding for 11 β-hydroxysteroid dehydrogenase type 2 leading to loss of enzyme activity have been confirmed in patients with apparent mineralocorticoid excess [31, 32].
Liddle’s syndrome is characterised by early presentation of moderate-to-severe hypertension with hypokalaemia, suppression of the renin-angiotensin system and low aldosterone levels [33]. Hypertension is caused by enhanced renal reabsorption of salt and water. Aldosterone antagonists are ineffective but reduction in blood pressure and correction of hypokalaemia by triamterene suggested an abnormality of the distal epithelial sodium channel. Patients with Liddle’s syndrome have gain-of-function mutations in the genes encoding either the β or γ subunits of the sodium channel which produce mutant subunits leading to a marked increase in sodium reabsorption in the distal convoluted tubule [34].
This autosomal dominant form of hypertension and hyperkalaemia, which is very responsive to thiazide diuretics, has recently been mapped to two distinct sites on chromosomes 1 and 17 [35, 36]. This suggests there may be more than one cause for this disorder, which may include a renal ion channel abnormality [36]. In this context it is interesting that rat and human comparative mapping studies have identified a locus on the long arm of chromosome 17 which maps to the same region as one of the loci for Gordon’s syndrome [37].
In this monogenetic syndrome, hypertension and brachydactyly are always inherited together (100% cosegregation) [38]. Affected persons are shorter than nonaffected relatives. The gene for hypertension has been mapped to the shorter arm of chromosome 12 (12p) in a large Turkish kindred [38]. Two other families with this syndrome have been reported, one in Canada and one in the United States [39]. In addition, the study of a Japanese child with hypertension and brachydactyly has allowed the area on 12p containing the gene mutation to be pinpointed further, although the gene responsible for this syndrome has not yet been cloned. Unlike the other 4 autosomal forms of hypertension, BP is not affected by volume expansion and the underlying mechanism is not known. Thus identification of the gene responsible may help clarify some of the genetic alterations in essential hypertension.
© 2001 Alexander Binder