The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme

Curnow, Kathleen M.; Mulatero, Paolo; Emeric-Blanchouin, N; Aupetit-Faisant, B.; Corvol, Pierre; Pascoe, Leigh

doi:10.1038/nsb0197-32

Cited by 91 publications

(40 citation statements)

References 27 publications

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“…In particular, there was no mutation or gene conversion involving sequences of exons 5 and 6 responsible for 18-hydroxylase and 18-oxidase activities. 15,20 Moreover, in all three GRA subjects we detected the same V386A polymorphism in the chimaeric portion of CYP11B2. This polymorphism is known to cause only minimal impairment of aldosterone synthase activity in vitro, 21 and has not been seen as an isolated homozygous change in patients with corticosterone methyloxidase type I or II deficiency.…”

Section: Discussionsupporting

confidence: 59%

Coexistence of different phenotypes in a family with glucocorticoid-remediable aldosteronism

et al. 2003

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In glucocorticoid-remediable aldosteronism (GRA), there is a large interfamily variation of phenotype. We report three subjects with GRA in a single family (parents, two brothers and two sisters), of whom only one (proband) displayed classical features of the mineralocorticoid excess. The proband was a man found to be hypertensive and hypokalaemic at the age of 24 years. Plasma renin activity was suppressed and plasma aldosterone was repeatedly elevated. Blood pressure and aldosterone levels normalized within 5 days of dexamethasone therapy. The presence of a chimaeric CYP11B1/CYP11B2 gene was demonstrated by long-PCR and Southern blotting (crossover site at the end of intron 3) in the proband, in the younger sister (sibling 1) and in the father. In these patients, sequencing of the chimaeric portion of CYP11B1 did not reveal any mutation, while sequencing of the chimaeric portion of CYP11B2 showed a V386A polymorphism in exon 7, known to cause only a minimal impairment of enzymatic activity. Sibling 1 was normotensive, normokalaemic and had normal PRA and aldosterone. The father had normal blood pressure and potassium, low-normal PRA and normal aldosterone. All three subjects had elevated levels of urinary 18-hydroxycortisol and 18-oxocortisol. Baseline 11-deoxycorticosterone (DOC), corticosterone (B) and aldosterone were high in the proband and normal in the father and sibling 1; 11-deoxycortisol (S) and cortisol (F) were normal. ACTH induced a normal increase of B, DOC, S and F, and an excessive aldosterone increase in all three patients. Abnormalities in the chimaeric portions of CYB11B1 or CYP11B2 genes did not account for the phenotypic disparity of the different members in a single GRA family. Altered regulation of the chimaeric gene may be responsible for differences in its activity.

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Section: Discussionsupporting

confidence: 59%

Coexistence of different phenotypes in a family with glucocorticoid-remediable aldosteronism

et al. 2003

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“…Amino acid residues have been identified in a recent study using transfection experiments with cDNAs which encode hybrids between the highly homologous cytochrome P450 enzymes, CYP11B1 (11b-hydroxylase) and CYP11B2 (aldosterone synthase), determining the different catalytic activities of both enzymes. Efficient 18-hydroxylation requires a glycine residue at position 288, and the subsequent 18-oxidation requires an alanine at position 320 (17). Thus, it can be stated that the heterozygous V386A mutation is not the cause of the patient's phenotype.…”

Section: European Journal Of Endocrinology (1998) 139mentioning

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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“…Multiple studies have located residues that distinguish the activities of these two enzymes. Residues 288, 296, 301, 302, 320 and 325 are critical [130,131]; these residues lie in or near the I-helix, and are expected to alter activesite geometry. Studies in vitro suggest that changing Ser288 and Val320 would be sufficient to distinguish between the two enzyme activities [130].…”

Section: Rstbroyalsocietypublishingorg Phil Trans R Soc B 368: 2012mentioning

confidence: 99%

Human cytochromes P450 in health and disease

Nebert

Wikvall

Miller

2013

Phil. Trans. R. Soc. B

426

305

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There are 18 mammalian cytochrome P450 (CYP) families, which encode 57 genes in the human genome. CYP2, CYP3 and CYP4 families contain far more genes than the other 15 families; these three families are also the ones that are dramatically larger in rodent genomes. Most (if not all) genes in the CYP1, CYP2, CYP3 and CYP4 families encode enzymes involved in eicosanoid metabolism and are inducible by various environmental stimuli (i.e. diet, chemical inducers, drugs, pheromones, etc.), whereas the other 14 gene families often have only a single member, and are rarely if ever inducible or redundant. Although the CYP2 and CYP3 families can be regarded as largely redundant and promiscuous, mutations or other defects in one or more genes of the remaining 16 gene families are primarily the ones responsible for P450-specific diseases-confirming these genes are not superfluous or promiscuous but rather are more directly involved in critical life functions. P450-mediated diseases comprise those caused by: aberrant steroidogenesis; defects in fatty acid, cholesterol and bile acid pathways; vitamin D dysregulation and retinoid (as well as putative eicosanoid) dysregulation during fertilization, implantation, embryogenesis, foetogenesis and neonatal development.

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The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme

Abstract: Transfection studies with cDNAs encoding hybrids between the highly similar cytochrome P450 enzymes, CYP11B1 (steroid 11 beta-hydroxylase) and CYP11B2 (aldosterone synthase) have identified which amino acids determine the different activities of the enzymes.

Cited by 91 publications

References 27 publications

Coexistence of different phenotypes in a family with glucocorticoid-remediable aldosteronism

Coexistence of different phenotypes in a family with glucocorticoid-remediable aldosteronism

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

Human cytochromes P450 in health and disease

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