Sex and the Single Gene—FH-1

John W. Funder

Baker Medical Research Institute Melbourne 8008, Victoria, Australia

Address correspondence and requests for reprints to: John W. Funder, M.D., Director, Baker Medical Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne 8008, Victoria, Australia.


    Introduction
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 Introduction
 References
 
The condition of familial hyperaldosteronism type 1 (FH-1) was first described by John Laidlaw and his colleagues (1) over three decades ago, as a syndrome of glucocorticoid-suppressible hyperaldosteronism, or perhaps preferably glucocorticoid-remediable aldosteronism (GRA). Grim and Winberger (2) entitled their 1980 paper "Familial dexamethasone-suppressible, normokalemic hyperaldosteronism," noting not only the familial and glucocorticoid-suppressible aspects of the hyperaldosteronism, but the common finding in such patients of potassium levels within the normal range, in contrast with the prevailing wisdom for primary aldosteronism due to adrenal adenoma or hyperplasia. "FDSNH" never had a future as a catchy abbreviation, and the second landmark study in the area, by Lifton et al. (3), refers to the syndrome as glucocorticoid-remediable hyperaldosteronism.

If blood must be spilt, let it be over things other than nomenclature. The opening sentence of the paper under review by Stowasser et al. (4) begins "Glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type 1, FH-1) is caused by ...," which says it all: the syndrome of FH-1/glucocorticoid-suppressible hyperaldosteronism/GRA will be referred to as GRA or FH-1, indistinguishably and interchangeably for the purposes of this editorial.

The study by Lifton et al. (3) showed how the enzyme responsible for aldosterone synthesis (aldosterone synthase, or CYP11B2) is responsive to ACTH in the syndrome of GRA. Briefly, the founding effect is the formation of a chimeric gene at an ancestral meiosis, after a relatively minor misalignment of the two strands of DNA. Under such conditions, part of the aldosterone synthase gene recombines with part of the gene coding for the signature glucocorticoid biosynthetic enzyme (11ß hydroxylase, or CYP11B1). Such a recombination can happen because CYP11B1 and CYP11B2 lie next to one another on human chromosome 8, at q22 or arguably slightly more telomeric, and because they share an overall sequence identity of ~94%. When recombination occurs in such a way as to couple the 5' end of 11ß-hydroxylase to the "business end" of aldosterone synthase, the chimeric gene responds to ACTH (like CYP11B1) by expressing an enzyme that converts precursor (commonly deoxycorticosterone or corticosterone) to aldosterone.

There are two other things that follow. First, the sequence(s) specifying tissue-selective expression lie within the 5', CYP11B1-derived part of the chimeric gene, leading to expression in the zona fasciculata, where 11ß-hydroxylase is normally expressed and cortisol is produced. Cortisol, thus, becomes a substrate for the chimeric enzyme to produce marked elevations in steroids such as 18-oxocortisol, used as a diagnostic marker until the emergence of PCR-based screening. Second, just as cortisol secretion from the zona fasciculata is minimally angiotensin-responsive in vivo, that of aldosterone in GRA is also nonresponsive to AII, as noted previously (5) and demonstrated in the subset of patients tested in the present study (4).

In the present study, Stowasser et al. (4) report on a total of 26 patients with FH-1, of whom 9 have "mild" hypertension [blood pressure (BP) never <160/100] and 17 have "severe" hypertension (systolic BP >180 or diastolic BP >120, at least once). The group ranged in age from 14–78 yr and included 13 females and 14 males. Of the mild group, 7 of 9 were females but only 6 of 15 of the severe group, a statistically significant difference (P < 0.05), and one attributed by the authors to gender. In contrast, biochemical differences between the groups (or, rather, subgroups from each group) were subtle if present, leading to a difference in authority in the final sentence of the Discussion: "In conclusion, in this group of 26 patients with FH-1: 1) severity of hypertension was related to gender, with females relatively protected against the development of early onset or severe hypertension and its complications; and 2) the degree of hybrid gene expression may have influenced hypertension severity."

The evidence for the latter of these two conclusions is as follows. Despite no differences between the groups in terms of mean age, parental original of the hybrid gene, plasma [K+], upright plasma aldosterone concentrations, PRA, urinary 18-oxocortisol or urinary [Na+], two differences in addition to gender did emerge. First, in AII infusion studies, recumbent plasma aldosterone concentration levels in the "mild" group were lower (P < 0.05) both basally and after infusion. Second, although overall no differences were seen in plasma [K+] between groups, all six patients with frank hypokalemia (<3.5 meq/L) were in the "severe" group. It was noted by the authors, however, that whereas none were on diuretics at the time of study, four of the six patients had been within the previous 2 months.

On this evidence, the authors hypothesize that the differences between mild and severe hypertension in FH-1 may reflect subtle differences in responsivity of the chimeric gene to various factors, including estrogen, coupled with downstream differences between groups in mineralocorticoid receptors (MRs) and/or "second messengers" involved in aldosterone action. Such an interpretation seems perhaps overly linear, particularly when no urinary kallikrein values are reported, given the cited association of lower urinary kallikrein levels with more severe hypertension (6). On the other hand, the authors seem rather reticent in terms of their primary claim, that the severity of FH-1 is gender related. Indeed, it is; but, the relationship seems to be more than that of gender per se and to be squarely related to estrogen status of the women involved, as follows.

In the "mild group," in which seven of nine patients are female, the ages of the women are 23, 29, 38, 39, 43, 43, and 71 yr. One 43-yr-old was on an estrogen-containing oral contraceptive; importantly, the 71-yr-old was on hormone replacement therapy. Compare this profile with that of the six women in the "severe" group, whose ages were 14, 51, 56, 60, 60, and 78 yr. Of this group all but the first are presumably postmenopausal, with the obvious exception of the adolescent. This patient, however, falls into the severe group on the basis (at least) of her age, because one of the exclusion criteria for the mild group is age <18 yr; even in subtropical Queensland it is probable that she had not been exposed long to the estrogen levels produced by normal ovulatory cycles. To what extent the 78-yr-old at the other end of the age spectrum falls into the "severe" group on the basis of classification (for example, for being on >1 medication) is unclear. Whatever her inclusion criteria in extenso, 78 yr of age and still going, with a plasma [K+] of 3.3 meq/L, is not a bad inning for someone with the severe form of a familial disease. Gender is one thing, and estrogen is something else: in the opinion of this reviewer, the authors have made a very good case for a role for estrogen in addition to that of gender, not at all necessarily via an effect on aldosterone secretion or action. Even those of us for whom aldosterone rules, okay, can probably admit additional ways to modulate blood pressure, in which estrogen can be and in all probability is physiologically involved.

Finally, three points. First, the very high incidence of death from stroke rather than heart attack has previously been studied in some detail (7) and is confirmed by the family history of members of the groups currently under study. The etiology of this propensity to stroke is yet to be established; what may be relevant are recent animal studies from Rocha et al. (8). They showed that administration of the MR antagonist spironolactone (Aldactone) to stroke-prone spontaneously hypertensive rats completely abolished the normal 100% mortality at 18–20 weeks of age, with no effect on blood pressure (8). Second, again from animal studies, the site of action of aldosterone in elevating BP has shifted from the kidney and Na+ retention to include a necessary contribution from the central nervous system. Gomez-Sanchez et al. (9) have shown that minute, peripherally totally ineffective doses of aldosterone infused intracerebroventricularly raise BP. Conversely, intracerebroventricular infusion of the MR antagonist RU28318, again at peripherally ineffective doses, blocks the hypertensinogenic effect of 6% NaCl feeding to John Rapp salt-sensitive rats (10). The hypertensinogenic effect of intracerebroventricular aldosterone can be progressively blocked by coinfused corticosterone, the physiologic glucocorticoid in rats (9), evidence for an antagonist effect of the physiologic glucocorticoids on the central mechanisms, and perhaps prompting a finer grained evaluation of cortisol to aldosterone ratios than attempted, to date, for GRA.

Finally, that GRA can occur offers us a point for reflection. It can occur because the genes for CYP11B1—you are going to be a glucocorticoid—and for CYP11B2—here comes the signature aldehyde (CHO) group on carbon 18—lie next to one another on human chromosome 8, and are 94% identical. Compare this with MRs and glucocorticoid receptors (GRs). The genes are on different chromosomes (MR, 4q 31.2; GR, 5q 31), and share variable homology. MRs and GRs are 90% identical in the DNA-binding domain, 57% in the ligand-binding domain, and <15% in the N-terminal half or more of the protein. The most common explanation for genes that lie next to one another and are highly homologous is that this represents relatively recent gene duplication event. Although MRs and GRs are clearly related, it would seem that they branched from a primordial ancestor well before CYP11B1 and CYP11B2. What this means is that MRs, for which we have assumed the "cognate" ligand is aldosterone, is actually, in evolutionary terms, much more ancient than the Johnny-come-lately aldosterone. This has been borne out by the recent cloning of rainbow trout MR (11), in a species that does not make aldosterone, and points to a physiological role for MRs as high-affinity GRs in nonepithelial tissues where the glucocorticoid-excluding enzyme 11ßHSD2 is not expressed (12). Whereas the experimental sequelae of aldosterone occupying such nonepithelial MRs are beginning to be charted (8, 9, 13, 14), their physiologic roles, and their particular relevance to clinical syndromes such as GRA, remain to be comprehensively addressed.

Received April 17, 2000.

Accepted April 17, 2000.


    References
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 Introduction
 References
 

  1. Sutherland DJA, Ruse JL, Laidlaw JC. 1966 Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J. 95:1109–1119.[Medline]
  2. Grim CE, Weinberger MH. 1980 Familial, dexamethasone-suppressible, normokalemic hyperaldosteronism. Pediatrics. 65:597–604.[Abstract]
  3. Lifton RP, Dluhy RG, Powers M, et al. 1992 A chimaeric 11ß-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 355:262–265.[CrossRef][Medline]
  4. Stowasser M, Bachmann AW, Huggard PR, Rossetti TR, Gordon RD. 2000 Severity of hypertension in familial hyperaldosteronism type I: relationship to gender and degree of biochemical disturbance. J Clin Endocrinol Metab. 85:2160–2166.[Abstract/Free Full Text]
  5. Stowasser M, Huggard PR, Rossetti TR, Bachmann AW, Gordon RD. 1999 Biochemical evidence of aldosterone overproduction and abnormal regulation in normotensive individuals with familial hyperaldosteronism type I. J Clin Endocrinol Metab. 84:4031–4036.[Abstract/Free Full Text]
  6. Dluhy RG, Lifton RP. 1995 Glucocorticoid-remediable aldosteronism (GRA): diagnosis, variability of phenotype and regulation of potassium homeostasis. Steroids. 60:48–51.[CrossRef][Medline]
  7. Litchfield WR, Anderson BF, Weiss RJ, Lifton RP, Dluhy RG. 1998 Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension. 31:445–450.[Abstract/Free Full Text]
  8. Rocha R, Chander PN, Khanna K, Zuckermann A, Stier Jr CT. 1998 Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension. 31:451–458.[Abstract/Free Full Text]
  9. Gomez-Sanchez EP, Venkataraman MT, Thwaites D, Fort C. 1990 ICV infusion of corticosterone antagonizes ICV-aldosterone hypertension. Am J Physiol. 258:E649–E653.
  10. Gomez-Sanchez EP, Fort C, Thwaites D. 1992 Central mineralocorticoid receptor antagonism blocks hypertension in Dahl S/JR rats. Am J Physiol. 262:E96–E99.
  11. Colombe L, Fostier A, Bury N, Pakdel F, Guiguen Y. 2000 A mineralocorticoid-like receptor in the rainbow trout, Oncorhynchus mykiss: cloning and characterization of its steroid binding domain. Steroids. In press.
  12. Funder JW, Krozowski S, Myles K, et al. 1997 Mineralocorticoid receptors, salt and hypertension. Recent Prog Horm Res. 52:247–262.[Medline]
  13. Brilla CG, Weber KT. 1992 Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med. 120:893–901.[Medline]
  14. Young M, Head G, Funder J. 1995 Determinants of cardiac fibrosis in experimental hypermineralocorticoid states. Am J Physiol. 269:E657–E662.




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