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(Hypertension. 1996;28:927-936.)
© 1996 American Heart Association, Inc.
Articles |
Inherited Forms of Mineralocorticoid Hypertension
the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas.
Correspondence to Dr Perrin C. White, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9063. E-mail pwhit2@mednet.swmed.edu.
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Abstract |
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 Top Abstract IntroductionHypertensive Forms of Congenital...Glucocorticoid-Suppressible...Loss of Specificity of...References |
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Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal distal convoluted tubules and cortical collecting ducts. Excess secretion of aldosterone or other mineralocorticoids or abnormal sensitivity to mineralocorticoids may result in hypertension, suppressed plasma renin activity, and hypokalemia. Such conditions often have a genetic basis, and studies of these conditions have provided valuable insights into the normal and abnormal physiology of mineralocorticoid action. Deficiencies of steroid 11ß-hydroxylase or 17
-hydroxylase are types of congenital adrenal hyperplasia, the autosomal recessive inability to synthesize cortisol. These two defects often cause hypertension because of overproduction of cortisol precursors that are, or are metabolized to, mineralocorticoid agonists. These disorders result from mutations in the CYP11B1 and CYP17 genes encoding the corresponding enzymes. Glucocorticoid-suppressible hyperaldosteronism is an autosomal dominant form of hypertension in which aldosterone secretion is abnormally regulated by corticotropin. It is caused by recombinations between linked genes encoding closely related isozymes, 11ß-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), generating a dysregulated chimeric gene with aldosterone synthase activity. Apparent mineralocorticoid excess is a loss of functional ligand specificity of the mineralocorticoid receptor caused by a deficiency of the kidney isozyme of 11ß-hydroxysteroid dehydrogenase, an enzyme that normally metabolizes cortisol to cortisone to prevent cortisol from occupying the receptor. This autosomal recessive form of severe hypertension results from mutations in the HSD11K (HSD11B2) gene.
Key Words: aldosterone • mineralocorticoids • hydroxylases • hydroxysteroid dehydrogenases • cytochrome P-450
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Introduction |
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TopAbstractIntroductionHypertensive Forms of Congenital...Glucocorticoid-Suppressible...Loss of Specificity of...References |
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Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal distal tubules and cortical collecting ducts, where it acts to increase sodium resorption from and potassium excretion into urine (Fig 1
, reviewed in Reference 1). Excess secretion of aldosterone or other mineralocorticoids or abnormal sensitivity to mineralocorticoids may result in hypokalemia, suppressed plasma renin activity, and hypertension. Such conditions often have a genetic basis, and studies of these conditions have provided valuable insights into the normal and abnormal physiology of mineralocorticoid action. This article reviews recent work in this area.
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Hypertensive Forms of Congenital Adrenal Hyperplasia |
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TopAbstractIntroductionHypertensive Forms of Congenital...Glucocorticoid-Suppressible...Loss of Specificity of...References |
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Synthesis of Aldosterone and Cortisol
Aldosterone is synthesized in the zona glomerulosa (the outermost zone) of the adrenal cortex through the actions of four enzymes (Fig 2
). The first three enzymes, cholesterol desmolase, 3ß-hydroxysteroid dehydrogenase, and 21-hydroxylase, are also required for synthesis of cortisol, the main glucocorticoid in humans, in the zona fasciculata. Cortisol biosynthesis, however, also requires 17-hydroxylation as the second step of the pathway.
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Although cortisol and aldosterone syntheses both require 11ß-hydroxylation of steroid intermediates, these steps are catalyzed by different isozymes, respectively termed steroid 11ß-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) (reviewed in Reference 2). These are both mitochondrial cytochromes P450—heme-containing, membrane-bound enzymes with molecular weights of approximately 50 kD. The latter isozyme catalyzes the subsequent 18-hydroxylation and 18-oxidation steps required for aldosterone synthesis as well as 11ß-hydroxylation and thus itself converts deoxycorticosterone to aldosterone.
Congenital adrenal hyperplasia, the inherited inability to synthesize cortisol, can be caused by mutations in any of four enzymes (Fig 2
) or by mutations in the steroidogenic acute regulatory protein required for cholesterol transport into mitochondria.3 More than 90% of cases are caused by 21-hydroxylase deficiency. This usually affects both aldosterone and cortisol biosynthesis, leading to signs of aldosterone deficiency, including hyponatremia, hyperkalemia, and hypovolemia, that may, if untreated, progress to shock and death within weeks after birth. In contrast, most remaining cases of congenital adrenal hyperplasia are associated with hypertension. Most of these are caused by 11ß-hydroxylase deficiency and a few by 17-hydroxylase deficiency (reviewed below). These autosomal recessive disorders represent the first mendelian forms of hypertension in which the affected genes were cloned and causative mutations identified (References 2 and 4 provide detailed reviews).
Clinical Presentation of 11ß-Hydroxylase Deficiency
In most populations, 11ß-hydroxylase deficiency comprises approximately 5% to 8% of cases of congenital adrenal hyperplasia; thus, it occurs in approximately 1 in 200 000 births. A large number of cases of 11ß-hydroxylase deficiency have been reported in Israel among Jewish immigrants from Morocco; the incidence in this group is currently estimated to be 1 in 5000 to 1 in 7000 births,5 presumably representing a founder effect.
In 11ß-hydroxylase deficiency, 11-deoxycortisol and deoxycorticosterone are not efficiently converted to cortisol and corticosterone, respectively. Decreased production of glucocorticoids reduces their feedback inhibition on the hypothalamus and anterior pituitary, increasing secretion of corticotropin. This stimulates the zona fasciculata of the adrenal cortex to overproduce steroid precursors proximal to the blocked 11ß-hydroxylase step. Thus, 11ß-hydroxylase deficiency can be diagnosed by detecting high basal or corticotropin-stimulated levels of deoxycorticosterone and/or 11-deoxycortisol in serum or increased excretion of the tetrahydro metabolites of these compounds in a 24-hour urine collection. Obligate heterozygous carriers of 11ß-hydroxylase deficiency alleles (eg, parents) have no consistent biochemical abnormalities detectable even after stimulation of the adrenal cortex with intravenous corticotropin,6 consistent with an autosomal recessive mode of inheritance.
Approximately two thirds of patients with the severe "classic" form of 11ß-hydroxylase deficiency have high blood pressure,5 often beginning within the first few years of life. Although the hypertension is usually of mild to moderate severity, left ventricular hypertrophy, retinopathy, or both have been observed in up to one third of patients, and deaths from cerebrovascular accidents have been reported.5 Other signs of mineralocorticoid excess such as hypokalemia and muscle weakness or cramping occur in a minority of patients and are not well correlated with blood pressure. Plasma renin activity is usually suppressed in older children, and aldosterone levels are consequently low even though the ability to synthesize aldosterone is actually unimpaired.
The cause of hypertension in 11ß-hydroxylase deficiency is not well understood. It might be assumed that it is caused by elevated serum levels of deoxycorticosterone, but blood pressure and deoxycorticosterone levels are poorly correlated in patients.7 In addition, this steroid has only weak mineralocorticoid activity when administered to humans or animals. Perhaps other metabolites of deoxycorticosterone are responsible for the development of hypertension. The 18-hydroxy and 19-nor metabolites of deoxycorticosterone are thought to be more potent mineralocorticoids,8 but consistent elevation of these steroids in 11ß-hydroxylase deficiency has not been documented. Moreover, synthesis of these steroids requires hydroxylations within the adrenal (19-nor-deoxycorticosterone is synthesized via 19-hydroxy and 19-oic intermediates) that are probably mediated primarily by CYP11B1.9 This is unlikely to occur efficiently in 11ß-hydroxylase deficiency.
In addition to hypertension, patients with 11ß-hydroxylase deficiency often exhibit signs of androgen excess. This occurs because accumulated cortisol precursors in the adrenal cortex are shunted (through the activity of 17-hydroxylase/17,20-lyase) into the pathway of androgen biosynthesis, which is active in the human adrenal in both sexes. Affected females are born with some degree of masculinization of their external genitalia. This includes clitoromegaly and partial or complete fusion of the labioscrotal folds. Such ambiguous genitalia can be difficult to distinguish from those of a normal cryptorchid male. In contrast to the external genitalia, the gonads and internal genital structures (fallopian tubes, uterus, and cervix) arising from the mullerian ducts are normal, and affected females have intact reproductive potential if their external genital abnormalities are corrected surgically.
Other signs of androgen excess that occur postnatally in both sexes include rapid somatic growth in childhood and accelerated skeletal maturation, leading to premature closure of the epiphyses and short adult stature. Additionally, patients may have premature development of sexual and body hair (premature adrenarche) and acne. Androgens may affect the hypothalamic-pituitary-gonadal axis, leading to amenorrhea or oligomenorrhea in females and true precocious puberty or, conversely, poor spermatogenesis in males.10
Glucocorticoid administration (usually with hydrocortisone) both replaces deficient cortisol and reduces corticotropin secretion, suppressing excessive adrenal androgen production and preventing further virilization. Such therapy should also suppress corticotropin-dependent production of mineralocorticoid agonists and ameliorate hypertension. If hypertension has been of long standing before treatment, additional antihypertensive drugs may be required to lower blood pressure into the normal range. These may include potassium-sparing diuretics such as spironolactone or amiloride and/or a calcium channel blocker such as nifedipine.11 Because the renin-angiotensin system is suppressed in these patients, angiotensin-converting enzyme inhibitors are unlikely to be effective. Thiazide diuretics should not be used except in combination with a potassium-sparing diuretic because they will otherwise cause hypokalemia in patients with mineralocorticoid excess.
Genetic Analysis of 11ß-Hydroxylase Deficiency
In humans, CYP11B1 and CYP11B2 are encoded by two genes12 on chromosome 8q21-q2213 14 (Fig 3). The nucleotide sequences of these genes are 95% identical in coding sequences and about 90% identical in introns. The genes are approximately 40 kb apart,15 16 and CYP11B2 is on the left if the genes are pictured as being transcribed left to right.17 These genes are regulated differently. CYP11B1 expression is stimulated by corticotropin, whereas the main stimuli of CYP11B2 expression are angiotensin II and potassium.18
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, deletion of nucleotides. For example, W116X represents a nonsense mutation of Trp-116.
11ß-Hydroxylase Deficiency Results From Mutations in CYP11B1
At this time, 20 mutations have been identified in patients with classic 11ß-hydroxylase deficiency.19 20 21 22 In Moroccan Jews, a group that has a high prevalence of 11ß-hydroxylase deficiency, almost all affected alleles carry the same mutation: Arg-448 to His (R448H).23 This and all other missense mutations identified thus far are in regions of known functional importance24 25 26 and abolish enzymatic activity.20 For example, Arg-448 is adjacent to Cys-450, which is a ligand of the heme iron atom of this cytochrome P450 enzyme. Other mutations found in patients with the classic form of the disease are nonsense or frameshift mutations that also abolish enzymatic activity.
No genetic studies of patients with mild nonclassic disease have been published yet, but unpublished work in our laboratory suggests that mutations causing this disorder reduce but do not destroy activity.
Although classic patients apparently completely lack 11ß-hydroxylase activity, they differ significantly in the severity of the various signs and symptoms of their disease. Moreover, there is no consistent correlation between the severity of hypertension and degree of virilization. These phenotypic variations must be governed by factors outside the CYP11B1 locus.
Clinical Presentation of 17-Hydroxylase Deficiency
Because cortisol cannot be synthesized, 17-deoxysteroids are synthesized in excessive quantities. Corticosterone, a glucocorticoid agonist, can be synthesized in the affected gland so that affected individuals do not suffer from adrenal insufficiency. However, adequate levels of corticosterone are synthesized only at the expense of excessive secretion of deoxycorticosterone, so patients with 17-hydroxylase deficiency tend to develop hypertension similar to that seen in 11ß-hydroxylase deficiency (reviewed in References 4 and 27). These forms of congenital adrenal hyperplasia are distinguished by signs of sex hormone deficiency in 17-hydroxylase deficiency in contrast to the androgen excess seen in 11ß-hydroxylase deficiency. The lack of sex hormones seen in 17-hydroxylase deficiency may not be apparent until the age at which puberty normally occurs, because prepubertal females appear normal and genetic males can have external genitalia indistinguishable from those of a female.
Genetic Analysis of 17-Hydroxylase Deficiency
The affected enzyme, a microsomal cytochrome P450, is encoded by the CYP17 gene on chromosome 10q24-25.28 29 30 At this time, at least 18 different mutations have been identified in 27 individuals (Fig 4, reviewed in References 4 and 31). All known mutations are in coding regions and range from simple missense mutations to wholesale replacement of exons by extraneous DNA. A 4-bp duplication in the last exon causing a shift in the reading frame has been found in 10 patients in the Netherlands or of Dutch Mennonite ancestry; this presumably represents a founder effect. Most of these mutations completely destroy enzymatic activity when mutant enzymes are expressed in bacteria or cultured mammalian cells, although a few mutations do retain partial activity and are associated with less severe signs of hypertension and androgen deficiency.
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Glucocorticoid-Suppressible Hyperaldosteronism |
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Clinical Presentation
Glucocorticoid-suppressible hyperaldosteronism (GSH) (also called dexamethasone-suppressible hyperaldosteronism or glucocorticoid-remediable aldosteronism) is a form of hypertension inherited in an autosomal dominant manner with high penetrance.32 33 It is characterized by moderate hypersecretion of aldosterone, suppressed plasma renin activity, and rapid reversal of these abnormalities after glucocorticoid administration. It is a rare disorder, with fewer than two dozen kindreds documented thus far (reviewed in Reference 34).
Hypokalemia is usually mild or absent. Levels of 18-hydroxycortisol and 18-oxocortisol are elevated to 20 to 30 times normal.35 The ratio of urinary excretion of tetrahydro metabolites of 18-oxocortisol to those of aldosterone exceeds 2.0, whereas this ratio averages 0.2 in normal individuals. Elevation of 18-oxocortisol is the most consistent and reliable biochemical marker of the disease. This steroid is an agonist for the mineralocorticoid receptor and has been shown to raise blood pressure in animal studies.36
Once an affected individual has been identified in a kindred, additional cases may be ascertained within that kindred with the use of biochemical (18-oxocortisol levels) or genetic (see below) markers.37 It is apparent from these studies that affected individuals have blood pressures that are markedly elevated compared with unaffected individuals in the same kindred, although some patients may in fact have normal blood pressures. Even young children typically have blood pressures greater than the 95th percentile for age, and most are frankly hypertensive before the age of 20 years. The hypertension is often only moderately severe, and blood pressures exceeding 180/120 mm Hg are unusual. Associated signs of hypertension are frequent, including left ventricular hypertrophy on the electrocardiogram and retinopathy. Some affected kindreds have remarkable histories of early (before age 45 years) death from stroke in many family members.37 38 Steroid biosynthesis is otherwise normal, so affected individuals have normal growth and sexual development.
Most laboratory and clinical abnormalities are suppressed by treatment with glucocorticoids, whereas corticotropin infusion exacerbates these problems.39 40 This suggests that aldosterone is being inappropriately synthesized in the zona fasciculata and is being regulated by corticotropin. Moreover, 18-hydroxycortisol and 18-oxocortisol, the steroids that are characteristically elevated in this disorder, are 17-hydroxylated analogues of 18-hydroxycorticosterone and aldosterone, respectively. Because 17-hydroxylase is not expressed in the zona glomerulosa, the presence of large amounts of a 17-hydroxy, 18-oxosteroid suggests that an enzyme with 18-oxidase activity (ie, aldosterone synthase, CYP11B2) is abnormally expressed in the zona fasciculata.
The initial treatment of choice in adults is dexamethasone (1 to 2 mg/d). Within 2 to 4 days of the initiation of therapy, oversecretion of aldosterone should be completely suppressed, and plasma renin activity and potassium (if low) should increase into the normal range. Blood pressure usually also decreases into the normal range. Children with this condition should be treated cautiously because of potential adverse effects of glucocorticoid therapy on growth. If therapy is indicated, children should be treated with the lowest effective dose of hydrocortisone. If hypertension is of long standing, it may not completely respond to glucocorticoids. This problem is similar to that observed in patients with 11ß-hydroxylase deficiency, and the choice of adjunctive therapy is governed by the same considerations. Patients with this disorder usually respond poorly to conventional antihypertensive medications unless they are also treated with glucocorticoids.
It is important to distinguish GSH from aldosterone-producing adenomas, considering that the latter condition is best treated by surgical removal of the affected adrenal gland.41 Secretion of 18-hydroxycortisol and 18-oxocortisol may be increased in patients with adenomas, but the ratio of urinary excretion of tetrahydro metabolites of 18-oxocortisol and aldosterone is rarely greater than 1.0.42 43 Suppression of aldosterone secretion with glucocorticoids42 and familial aggregation44 are both unusual findings in adenomas but have been reported. However, presentation of an adenoma during childhood is exceedingly rare. Conversely, rare patients with GSH eventually become resistant to glucocorticoids and are then indistinguishable from patients with primary aldosteronism.35 The mechanism by which this occurs is not known.
Genetic Analysis
All patients with GSH have the same type of mutation, that is, a chromosome that carries three CYP11B genes instead of the normal two.15 16 45 The middle gene on this chromosome is a chimera with 5' and 3' ends corresponding to CYP11B1 and CYP11B2, respectively. The chimeric gene is flanked by presumably normal CYP11B2 and CYP11B1 genes. In all kindreds analyzed thus far, the break points (the points of transition between CYP11B1 and CYP11B2 sequences) are located between intron 2 and exon 4. As the break points are not identical in different kindreds, these must represent independent mutations.
The invariable presence of a chimeric gene in patients with this disorder suggests that this gene is regulated like CYP11B1 (expressed at high levels in the zona fasciculata and regulated primarily by corticotropin) but has enzymatic activity like the aldosterone synthase enzyme encoded by CYP11B2. A single copy of such an abnormally regulated gene should be sufficient to cause the disorder, consistent with the known autosomal dominant mode of inheritance of this syndrome. Recently, abnormal expression of the chimeric gene in the zona fasciculata was directly demonstrated by in situ hybridization studies of an adrenal gland from a patient with this disorder.46
The chromosomes carrying chimeric genes are presumably generated by unequal crossing over. The high homology and proximity of the CYP11B1 and CYP11B2 genes make it possible for them to become misaligned during meiosis. If this occurs, crossing over between the misaligned genes creates two chromosomes, one of which carries one CYP11B gene (ie, a deletion) and the other three CYP11B genes.
The limited region in which crossover break points have been observed in GSH alleles suggests that there are functional constraints on the structures of chimeric genes able to cause this disorder. One obvious constraint is that sufficient CYP11B2 coding sequences must be present in the chimeric gene so that the encoded enzyme actually has aldosterone synthase (ie, 18-hydroxylase and 18-oxidase) activity. As determined by expression of chimeric cDNAs in cultured cells, chimeric enzymes with amino termini from CYP11B1 and carboxyl termini from CYP11B2 have 18-oxidase activity only if at least the region encoded by exons 5 through 9 corresponds to CYP11B2. If the sequence of exon 5 instead corresponds to CYP11B1, the enzyme has 11ß-hydroxylase but no 18-oxidase activity.15 This is entirely consistent with the observation that no break points in GSH alleles occur after exon 4. The chimeric enzymes either have strong 18-oxidase activity or none detectable, and there does not appear to be any location of crossover that yields an enzyme with an intermediate level of 18-oxidase activity. Thus, there is no evidence for allelic variation in this disorder (ie, variations in clinical severity are unlikely to be the result of different crossover locations).
Other factors such as bradykinin levels may affect the development of hypertension in this disorder.47 It appears that blood pressure in people with GSH is higher when the disease is inherited from the mother than when it is inherited from the father.48 It is theoretically possible that the gene is imprinted (ie, the maternal and paternal copies are expressed differently), but it is more likely that exposure of the fetus to elevated levels of maternal aldosterone subsequently exacerbates the hypertension.
The chimeric genes causing GSH can be readily detected by hybridization to Southern blots of genomic DNA, or they can be specifically amplified with the polymerase chain reaction. As these techniques are widely used in molecular genetics laboratories, direct molecular genetic diagnosis may be more practical in many cases than assays of 18-oxocortisol levels, which are not routinely available.
Although it originally seemed possible that a "mild" form of GSH might be a common etiology of essential hypertension, the lack of allelic variation in this disorder makes this unlikely. However, other polymorphisms in the 5' flanking region of CYP11B2 have been documented,45 49 although none has been shown to affect expression of the gene. If any does influence regulation of CYP11B2, it might be a risk factor for the development of hypertension. It has also been suggested that polymorphisms in the coding sequence of CYP11B2 might increase the aldosterone synthase activity of the enzyme and thus might be a risk factor for hypertension.50 Although such polymorphisms have been documented in rats, none has been found to occur naturally in humans.
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Loss of Specificity of the Mineralocorticoid Receptor: The Syndrome of Apparent Mineralocorticoid Excess |
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Clinical Features
Apparent mineralocorticoid excess (AME) is an inherited syndrome in which children present with hypertension, hypokalemia, and low plasma renin activity. Other clinical features include moderate intrauterine growth retardation and postnatal failure to thrive. Consequences of the often severe hypokalemia include nephrocalcinosis, nephrogenic diabetes insipidus, and rhabdomyolysis. Complications of hypertension have included cerebrovascular accidents, and several patients have died during infancy or adolescence. Several affected sibling pairs have been reported, but parents have usually been asymptomatic, suggesting that AME is a genetic disorder with an autosomal recessive mode of inheritance.
A low salt diet or blockade of mineralocorticoid receptors with spironolactone ameliorates the hypertension, whereas corticotropin and hydrocortisone exacerbate it. Levels of all known mineralocorticoids are low.51 52 These findings suggest that cortisol (ie, hydrocortisone) acts as a stronger mineralocorticoid than is normally the case. Indeed, patients with AME have abnormal cortisol metabolism. Cortisol half-life in plasma is prolonged from approximately 80 minutes to 120 to 190 minutes.51 Very low levels of cortisone metabolites are excreted in the urine compared with cortisol metabolites, indicating a marked deficiency in 11ß-hydroxysteroid dehydrogenase (11-HSD), the enzyme catalyzing the conversion of cortisol to cortisone. This has been assayed directly by administration of 11-[3H]cortisol to subjects and measurement of the appearance of tritiated water. Most often it is measured as an increase in the sum of the urinary concentrations of tetrahydrocortisol and allotetrahydrocortisol divided by the concentration of tetrahydrocortisone, abbreviated (THF+aTHF)/THE. However, 11-reduction is unimpaired; labeled cortisone administered to patients is excreted entirely as cortisol and other 11ß-reduced metabolites.53
Similar but milder abnormalities occur with licorice intoxication.54 The active component of licorice, glycyrrhetinic acid, inhibits 11-HSD in isolated rat kidney microsomes.55 Thus, it appears that licorice intoxication is a reversible pharmacological counterpart to the inherited syndrome of AME.
Why Does 11-HSD Deficiency Cause Hypertension?
Aldosterone regulates electrolyte excretion and intravascular volume mainly through its effects on the renal distal tubule and cortical collecting duct, where it acts to increase resorption of sodium from the urine through transcriptional effects mediated by a specific nuclear receptor referred to as the mineralocorticoid, or type 1, steroid receptor. These receptors are expressed in renal distal tubules and cortical collecting ducts and also in other mineralocorticoid target tissues, including salivary glands and the colon. The mineralocorticoid receptor has a high degree of sequence identity with the glucocorticoid, or type 2, receptor,56 and it has very similar in vitro binding affinities for aldosterone and for glucocorticoids such as corticosterone and cortisol.56 57 This seems paradoxical, because corticosterone and cortisol are weak mineralocorticoids in vivo.
It has been proposed54 58 59 that oxidation by 11-HSD of cortisol or corticosterone to cortisone or 11-dehydrocorticosterone, respectively, represents the physiological mechanism conferring specificity for aldosterone upon the mineralocorticoid receptor (Fig 1). Although cortisol and corticosterone bind the receptor well in vitro, cortisone and 11-dehydrocorticosterone are poor agonists for this receptor. Aldosterone is a poor substrate for 11-HSD because, in solution, its 11-hydroxyl group is normally in a hemiacetal conformation with the 18-aldehyde group. Thus, in AME or licorice intoxication, 11-HSD deficiency allows cortisol to occupy the mineralocorticoid receptor. Because cortisol normally circulates at levels 100 to 1000 times those of aldosterone, this leads to signs of mineralocorticoid excess even though aldosterone secretion is suppressed. This has now been confirmed by molecular studies of patients with AME.
Isozymes of 11-HSD
There are two distinct isozymes of 11-HSD. Both are members of the short-chain dehydrogenase family. These enzymes all have a highly conserved nucleotide cofactor binding domain near the amino terminus; the cofactor functions as an electron acceptor for dehydrogenation (NAD+ or NADP+) and an electron donor for reduction (NADH or NADPH). Completely conserved tyrosine and lysine residues toward the carboxyl terminus function in catalysis.
The first, termed the liver (L) or type I isozyme, was originally isolated from rat liver microsomes60 and the corresponding cDNA cloned.61 It requires NADP+ as a cofactor and has an affinity for steroids in the micromolar range. Although the enzyme purified from rat liver functions only as a dehydrogenase, the recombinant enzyme expressed from cloned cDNA exhibits both 11ß-dehydrogenase and the reverse oxoreductase activities (conversion of 11-dehydrocorticosterone to corticosterone) when expressed in mammalian cells,61 suggesting that the reductase activity is destroyed during purification from the liver.
Several lines of evidence suggest that this isozyme does not play a significant role in conferring ligand specificity on the mineralocorticoid receptor. It is expressed at highest levels in the liver, which does not respond to mineralocorticoids, and although it is expressed at high levels in the rat kidney,61 it is expressed at much lower levels in human kidneys.62 Even in rat kidney, immunoreactivity to the protein is observed primarily in proximal tubules and not in distal tubules and collecting ducts, the sites of mineralocorticoid action.63 Finally, when the HSD11ß1 gene encoding this isozyme was cloned62 and examined for mutations in patients with AME, none were found.64
Accordingly, a second isozyme was sought in mineralocorticoid target tissues. Evidence for such an isozyme was obtained from biochemical studies of isolated rabbit kidney cortical collecting duct cells.65 Activity of 11-HSD in the microsomal fraction was almost exclusively NAD+ dependent and had a very high affinity for steroids (Km for corticosterone of 26 nmol/L). There was almost no reduction of 11-dehydrocorticosterone to corticosterone, suggesting that, unlike the L isozyme, the kidney (K) or type II isozyme only catalyzed dehydrogenation. The enzyme in the human placenta had similar characteristics66 : it was NAD+ dependent and had Km values for steroids in the nanomolar range. Similar activities were noted in sheep kidney67 and many human fetal tissues.68
Thus far, the K isozyme has not been purified to homogeneity in active form from any source. This rendered the cloning of the corresponding cDNA more difficult. It was eventually accomplished by expression screening strategies in which pools of clones were assayed for their ability to confer NAD+-dependent 11-HSD activity on Xenopus oocytes or cultured mammalian cells. Positive pools were divided into smaller pools and rescreened until a single positive clone was identified. Both sheep69 and human70 cDNAs encoding this isoform were isolated in this manner. The recombinant K isozyme has properties that are virtually identical to the activity found in mineralocorticoid target tissues. The recombinant enzyme functions exclusively as a dehydrogenase; no reductase activity is detectable with either NADH or NADPH as a cofactor.69 70 It has an almost exclusive preference for NAD+ as a cofactor and a very high affinity for glucocorticoids. The K isozyme is expressed in mineralocorticoid target tissues, particularly the kidney, and in human placenta, whereas it is not detected in the liver.
The predicted amino acid sequence of the K isozyme is only 21% identical to that of the L isozyme of 11-HSD. The corresponding gene, termed HSD11K or HSD11B2, is located on chromosome 16q22.71 It differs in its intron-exon organization from HSD11L, suggesting that the two isozymes are only distantly related.
Detection of Mutations in HSD11K in Patients With AME
Thus far, 11 different mutations have been identified in the HSD11K gene in 15 kindreds with AME (Fig 5). These mutations all affect enzymatic activity or pre-mRNA splicing, thus confirming in its entirety the hypothesis that 11-HSD protects the mineralocorticoid receptor from high concentrations of cortisol.72 73 74 75 76 Only one patient has been a compound heterozygote for two different mutations, whereas all other patients have carried homozygous mutations. This suggests that the prevalence of AME mutations in the general population is low, so the disease is found mostly in limited populations in which inbreeding is relatively high. Six kindreds are of Native American origin. Three from Minnesota or Canada carry the same mutation (L250S, L251P), consistent with a founder effect, but the others are each homozygous for a different mutation. The reason for the relatively high prevalence of this very rare disease among Native Americans is not immediately apparent.
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Of the mutations identified thus far, two shift the reading frame of translation; a third deletes three amino acids, including the catalytic tyrosine residue (Y232); and one is a nonsense mutation. These mutations are all presumed to completely destroy enzymatic activity. One mutation in the third intron leads to skipping of the fourth exon during processing of pre-mRNA.72 As the fourth exon encodes the catalytic site, the resulting enzyme is again presumably inactive. The other six mutations have been introduced into cDNA and expressed in cultured cells for determination of their effects. One is completely inactive and one has only a trace of activity. The others are all partially active in cultured cells, with one, Arg-337 to Cys (R337C), having greater than 50% of normal activity.76 Only R337C is partially active in lysed cells (although one group reported this mutation to be inactive in cell lysates,77 they did not use conditions that would promote enzyme stability). Thus, most mutations of this enzyme adversely affect protein stability once cells are lysed; this has been confirmed by Western blots.76
Both the wild-type enzyme and most mutants are concentrated in the nucleus as determined by Western blots of cell fractions. This may reflect the function of the enzyme in protecting the nuclear mineralocorticoid receptor from excessive concentrations of cortisol.
Although the number of patients with AME is small, sufficient data now exist to demonstrate a statistically significant correlation between the degree of enzymatic impairment and biochemical severity as measured by the ratio of the precursor to the product, (THF+aTHF)/THE.76 This correlation is most obvious for the partially active mutants. We assume in this analysis that R337C is the only significant mutation in the patients who carry it, even though only one exon of the gene was sequenced.73 If so, a 50% impairment of enzymatic activity is apparently sufficient to compromise cortisol metabolism in the kidney, suggesting that this organ has very little excess capacity to metabolize cortisol. This seems to raise a paradox because AME is a recessive disorder and heterozygous carriers, who would be expected to have 50% of normal activity, are asymptomatic. Altered stability or kinetic properties of the R337C mutant, including alterations in enzyme inhibition by end product (ie, cortisone or corticosterone) or by other circulating steroids, may be important.
Because of the small numbers of patients and the possible confounding effects of prior antihypertensive therapy, it is difficult to correlate biochemical severity with measures of clinical severity, although anecdotal reports suggest that mutations that do not destroy activity may be associated with milder disease.72 73 With the elucidation of the molecular genetic basis of this disorder, ascertainment of additional cases may permit these questions to be answered.
Whereas apparent 11-HSD deficiency causes severe hypertension, it is reasonable to hypothesize that milder decreases in enzymatic activity might be associated with common "essential" hypertension. Patients with AME are often born with a mild to moderate degree of intrauterine growth retardation. Although the reason for this is not known, it seems likely that a deficiency of 11-HSD in the placenta permits excessive quantities of maternal glucocorticoids to cross the placenta and thus inhibit fetal growth.78 Thus, a hypothetical mild form of 11-HSD deficiency might also present with low birth weight and subsequent hypertension.79 In rats, placental 11-HSD activity is inversely correlated with placental weight and directly correlated with term fetal weight.80 In human population studies, most of which are retrospective, low birth weight and increased placental weight are indeed risk factors for the subsequent development of adult hypertension.81 Although variations in 11-HSD might in principle be responsible for this correlation, a recent study in humans82 did not find such a correlation between placental 11-HSD activity and placental weight. A weak but significant positive correlation was observed between 11-HSD activity and fetal birth weight, but a subsequent larger study of the identical population was unable to confirm this (F. Rogerson and P.C.W., unpublished observations, 1996). Thus, the currently available data do not support the idea that low 11-HSD activity is a risk factor for low birth weight in humans who do not suffer from AME. Of course, this doesn't rule out a possible effect of genetically determined mild variations in 11-HSD activity upon blood pressure. Molecular studies (analogous to those reviewed in Reference 83) of HSD11K should unambiguously determine whether this gene is frequently involved in the development of hypertension. These might include linkage studies (looking for increased identity by descent in hypertensive sib pairs) and a search for frequent polymorphisms in HSD11K that might be associated with the development of hypertension. Additional insights into the physiology of this enzyme might be obtained by "knocking out" the corresponding gene in mice.84
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Acknowledgments |
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This work was supported by grants DK37867 and DK42169 from the National Institutes of Health, Bethesda, Md.
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Footnotes |
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This article was presented by Perrin C. White as the Theodore Cooper Memorial Lecture on May 29, 1996, at the Alton Oehsner Medical Foundation, New Orleans, La, on May 29, 1996.
Received July 12, 1996; first decision July 16, 1996; accepted July 16, 1996.
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TopAbstractIntroductionHypertensive Forms of Congenital...Glucocorticoid-Suppressible...Loss of Specificity of...References |
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