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Screening for genetic causes of hypertension

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Abstract

Monogenic or single-gene forms of human hypertension result from mutations involving regulatory elements of the renin-angiotensin-aldosterone system (RAAS) or occur in syndromes associated with hereditary pheochromocytoma. RAAS gain-of-function mutations result in sodium retention, suppression of plasma renin activity, and often, but not invariably, hypokalemia. Hereditary RAAS syndromes result from intrinsic renal abnormalities (apparent mineralocorticoid excess and Liddle’ syndromes) or from mineralocorticoid excess states (congenital adrenal hyperplasia and glucocorticoid-remediable aldosteronism). In the hereditary pheochromocytoma syndromes many asymptomatic individuals are identified because they are at-risk individuals in kindreds with a pheochromocytoma-predisposing syndrome. On the other hand, up to 25% of subjects with presumed «sporadic" pheochromocytoma have germline mutations in one of four pheochromocytoma susceptibility genes (the RET proto-oncogene, von Hippel-Lindau gene, neurofibromatosis F1 gene, and succinate dehydrogenase subunit D and succinate dehydrogenase subunit B genes). Hereditary pheochromocytomas are typically intra-adrenal and bilateral and patients typically present at younger ages compared with sporadic pheochromocytoma.

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References and Recommended Reading

  1. Lifton RP, Gharavi AG, Geller DS: Molecular mechanisms of human hypertension. Cell 2001, 104:545–556. An indepth review of the molecular mechanisms and genetic mutations underlying human hypertension to date.

    Article  PubMed  CAS  Google Scholar 

  2. Dluhy RG: Pheochromocytoma - death of an axiom. N Engl J Med 2002, 346:1486–1488.

    Article  PubMed  Google Scholar 

  3. Funder JW, Pearce PT, Smith R, Smith AI: Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 1988, 242:583–585.

    Article  PubMed  CAS  Google Scholar 

  4. Liddle GW, Bledsoe T, Coppage WS Jr: A familial renal disorder simulating primary aldosterone but with negligible aldosterone secretion. Trans Assoc Am Physicians 1963, 76:199–213.

    CAS  Google Scholar 

  5. Shimkets RA, Warnock DG, Bositis CM, et al.: Liddle’ syndrome: heritable human hypertension caused by mutations in the b subunit of the epithelial sodium channel. Cell 1994, 79:407–414.

    Article  PubMed  CAS  Google Scholar 

  6. Geller DS, Farhi A, Pinkerton N, et al.: Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 2000, 289:119–123.

    Article  PubMed  CAS  Google Scholar 

  7. Wilson FH, Disse-Nicodeme S, Choate KA, et al.: Human hypertension caused by mutations in WNK kinases. Science 2001, 293:1107–1112. The molecular basis of pseudohypoaldosteronism type II results from mutations in the WNK family of serine-threonine kinases in the distal nephron. This results in the impaired excretion of hydrogen and potassium ions as well as increased sodium reabsorption. Thus, hypertension is seen in the setting of supressed PRA and hyperkalemia.

    Article  PubMed  CAS  Google Scholar 

  8. Curnow KM, Slutsker L, Vitek J, et al.: Mutations in the CYP11b 1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7, and 8. Proc Natl Acad Sci U S A 1993, 90:4552–4556.

    Article  PubMed  CAS  Google Scholar 

  9. Mune F, Rogerson FM, Nikkila H, et al.: Human hypertension is caused by mutations in the kidney isozyme of 11b-hydroxysteroid dehydrogenase. Nat Genet 1995, 10:394–399.

    Article  PubMed  CAS  Google Scholar 

  10. Yanase T, Simpson ER, Waterman MR: 17a-Hydroxylase/17,20 lyase deficiency: from clinical investigation to molecular definition. Endocrinol Rev 1991, 12:91–108.

    CAS  Google Scholar 

  11. Litchfield WR, Anderson BF, Weiss RJ, et al.: Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension 1998, 31(pt 2):445–450.

    PubMed  CAS  Google Scholar 

  12. Litchfield WR, New MI, Coolidge C, et al.: Evaluation of the dexamethasone suppression test for the diagnosis of glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab 1997, 82:3570–3573.

    Article  PubMed  CAS  Google Scholar 

  13. Lifton RP, Dluhy RG, Powers M, et al.: A chimaeric 11b-hydroxylase/ aldosterone synthase gene causes glucocorticoidremediable aldosteronism and human hypertension. Nature 1992, 355:262–265.

    Article  PubMed  CAS  Google Scholar 

  14. Lifton RP, Dluhy RG, Powers M, et al.: Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet 1992, 2:66–74.

    Article  PubMed  CAS  Google Scholar 

  15. Neumann HP, Bausch B: Germline mutatations in non-syndromic pheochromocytoma. N Engl J Med 2002, 346:1459–1466. Clinicians are taught that 90% of pheochromocytomas are sporadic or nonsyndromic. This study from two registries (West Germany and Poland) found germline mutations in one or four susceptibility genes in 25% of subjects with presumed ‘sporadic" pheochromocytoma.

    Article  PubMed  CAS  Google Scholar 

  16. Bravo EL, Gifford RW: Pheochromocytoma: diagnosis, localization and management. N Engl J Med 1984, 30:1682–1686.

    Google Scholar 

  17. Pacak K, Linehan WM, Eisenhofer G, et al.: Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 2001, 134:315–329. The use of plasma metanephrines to diagnose pheochromocytoma is encouraged by this group of investigators.

    PubMed  CAS  Google Scholar 

  18. Neumann HP, Berger DP, Sigmund G, et al.: Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 1993, 329:1531–1538.

    Article  PubMed  CAS  Google Scholar 

  19. Santoro M, Carlomagno F, Romano A, et al.: Activation of RET as a dominant transforming gene by germline mutations of MEN 2A and MEN 2B. Science 1995, 267:381–383.

    Article  PubMed  CAS  Google Scholar 

  20. Eng C, Crossey PA, Milligan LM, et al.: Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic pheochromocytomas. J Med Genet 1995, 32:934–937.

    Article  PubMed  CAS  Google Scholar 

  21. Baysal BE, Ferrell RE, Willett-Brozick JE, et al.: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000, 287:848–851. A gene mutation in succinate dehydrogenase subunit D is identified as a susceptibility gene for the autosomal dominant hereditary paraganglioma syndrome. Germline mutations of this gene are also seen in patients with ‘sporadic" or nonsyndromic pheochromocytoma.

    Article  PubMed  CAS  Google Scholar 

  22. Ackrell BA: Progress in understanding structure-function relationships in respiratory chain complex II. FEBS Lett 2000, 466:1–5.

    Article  PubMed  CAS  Google Scholar 

  23. Maxwell PH, Wiesener MS, Chang GW, et al.: The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999, 399:271–275. A possible mechanism for neoplastic transformation in VHL is a defect in the oxygen-sensing system as a result of the loss-of-function mutation in the VHL tumor suppressor protein.

    Article  PubMed  CAS  Google Scholar 

  24. Gimm O, Armanios M, Dziema H, et al.: Somatic and occult germline mutations in SDHD, a mitochondrial complex II gene, in non-familial pheochromocytomas. Cancer Res 2000, 60:6822–6825.

    PubMed  CAS  Google Scholar 

  25. Aguiar R, Cox G, Pomeroy S, Dahia P: Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas. J Clin Endocrinol Metab 2001, 86:2890–2894.

    Article  PubMed  CAS  Google Scholar 

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Dluhy, R.G. Screening for genetic causes of hypertension. Current Science Inc 4, 439–444 (2002). https://doi.org/10.1007/s11906-002-0023-4

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  • DOI: https://doi.org/10.1007/s11906-002-0023-4

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