Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency.

Pascoe, Leigh; Curnow, Kathleen M.; Slutsker, Liliya; Rösler, Ariel; White, Perrin C.

doi:10.1073/pnas.89.11.4996

Cited by 169 publications

(97 citation statements)

References 34 publications

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“…As a mirror image, patients with inborn errors in the biosynthesis of aldosterone present with salt wasting, severe hypotension, and a decreased distal tubular K + and H + secretion. Wellcharacterised syndromes include homozygous loss of aldosterone synthase activity (the actual mirror image of GRA) or 21-hydroxylase activity (Mitsuuchi et al 1992;Pascoe et al 1992b;Bongiovanni and Root 1963;Armor et al 1988).…”

Section: Monogenic Hypotensionmentioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

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Section: Monogenic Hypotensionmentioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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“…Within the small number of patients with congenital hypoaldosteronism due to aldosterone synthase deficiency, patients with CMO deficiency type I appear to have the more severely decreased enzyme activity of P450c11Aldo compared with those with CMO deficiency type II (8)(9)(10)(11)(12)(13). The stop mutation in exon 4 which was identified in the two brothers might explain the biochemical phenotype, because the predicted enzyme has lost the five terminal exons encoding for several a-helices and b-strands which contain important residues for proton transfer, accessory protein binding, haem binding and substrate binding (19).…”

Section: European Journal Of Endocrinology (1998) 139mentioning

confidence: 99%

“…Both disorders are characterised clinically by salt-wasting, failure to thrive and growth retardation. Molecular genetic analysis of the genomic DNA from CMO deficiency type I and II patients led to the identification of mutations in the CYP11B2 gene (8)(9)(10)(11)(12)(13). However, one study showed no CYP11B2 gene mutations in a patient with CMO deficiency type II (14).…”

Section: Introductionmentioning

confidence: 99%

Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

Peter

Bünger

Drop

et al. 1998

European Journal of Endocrinology

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We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2), presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

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“…The possible role of aldosterone was further evidenced by the finding that loss-and gainof function due to distinct gene variants of CYP11B2 may predispose for or protect from preeclampsia, respectively. In fact, the V386A variant of CYP11B2 gene, which causes a deficiency in the rate-limiting step of aldosterone synthesis, the 18-hydroxycorticosterone methyl oxidase activity [30], was observed solely in a subgroup of preeclamptic women, but never in normal pregnant women [35]. In contrast, the gain of function variants of the CYP11B2 gene in the SF-1 and Int2 (C) sites, which have been shown to be associated with hypertension in non-pregnant subjects [26], apparently reduce the risk of developing preeclampsia [8].…”

Section: Introductionmentioning

confidence: 99%

Aldosterone deficiency adversely affects pregnancy outcome in mice

Todkar

Chiara

Loffing‐Cueni

et al. 2012

Pflugers Arch - Eur J Physiol

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Circulating aldosterone levels are increased in human pregnancy. Inadequately low aldosterone levels as present in preeclampsia, a life-threatening disease for both mother and child, are discussed to be involved in its pathogenesis or severity. Moreover, inactivating polymorphisms in the aldosterone synthase gene have been detected in preeclamptic women. Here, we used aldosterone synthase-deficient (AS(-/-)) mice to test whether the absence of aldosterone is sufficient to impair pregnancy or even to cause preeclampsia. AS(-/-) and AS(+/+) females were mated with AS(+/+) and AS(-/-) males, respectively, always generating AS(+/-) offspring. With maternal aldosterone deficiency in AS(-/-) mice, systolic blood pressure was low before and further reduced during pregnancy with no increase in proteinuria. Yet, AS(-/-) had smaller litters due to loss of fetuses as indicated by a high number of necrotic placentas with massive lymphocyte infiltrations at gestational day 18. Surviving fetuses and their placentas from AS(-/-) females were smaller. High-salt diet before and during pregnancy increased systolic blood pressure only before pregnancy in both genotypes and abolished the difference in blood pressure during late pregnancy. Litter size from AS(-/-) was slightly improved and the differences in placental and fetal weights between AS(+/+) and AS(-/-) mothers disappeared. Overall, an increased placental efficiency was observed in both groups paralleled by a normalization of elevated HIF1 levels in the AS(-/-) placentas. Our results demonstrate that aldosterone deficiency has profound adverse effects on placental function. High dietary salt intake improved placental function. In this animal model, aldosterone deficiency did not cause preeclampsia. ABSTRACTCirculating aldosterone levels are increased in human pregnancy. Inadequately low aldosterone levels as present in preeclampsia, a life-threatening disease for both mother and child, are discussed to be involved in its pathogenesis or severity.Moreover, inactivating polymorphisms in the aldosterone synthase gene have been detected in preeclamptic women. Here, we used aldosterone synthase deficient

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Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency.

Cited by 169 publications

References 34 publications

Genetics of arterial hypertension and hypotension

Genetics of arterial hypertension and hypotension

Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

Aldosterone deficiency adversely affects pregnancy outcome in mice

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