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

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

Research output: Contribution to journalArticle

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Abstract

Corticosterone methyloxidase II (CMO-II) deficiency is an autosomal recessive disorder of aldosterone biosynthesis, characterized by an elevated ratio of 18-hydroxycorticosterone to aldosterone in serum. It is genetically linked to the CYP11B1 and CYP11B2 genes that, respectively, encode two cytochrome P450 isozymes, P450XIB1 and P450XIB2. Whereas P450XIB1 only catalyzes hydroxylation at position 11β of 11-deoxycorticosterone and 11-deoxycortisol, P450XIB2 catalyzes the synthesis of aldosterone from deoxycorticosterone, a process that successively requires hydroxylation at positions 11β and 18 and oxidation at position 18. To determine the molecular genetic basis of CMO-II deficiency, seven kindreds of Iranian-Jewish origin were studied in which members suffered from CMO-II deficiency. No mutations were found in the CYP11B1 genes, but two candidate mutations, R181W and V386A, were found in the CYP11B2 genes. When these mutations were individually introduced into CYP11B2 cDNA and expressed in cultured cells, R181W reduced 18-hydroxylase and abolished 18-oxidase activities but left 11β-hydroxylase activity intact, whereas V386A caused a small but consistent reduction in the production of 18-hydroxycorticosterone. All individuals affected with CMO-II deficiency were homozygous for both mutations, whereas eight asymptomatic subjects were homozygous for R181W alone and three were homozygous for V386A alone. These findings confirm that P450XIB2 is the major enzyme mediating oxidation at position 18 in the adrenal and suggest that a small amount of residual activity undetectable in in vitro assays is sufficient to synthesize normal amounts of aldosterone.

Original languageEnglish (US)
Pages (from-to)4996-5000
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number11
StatePublished - 1992

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Cytochrome P-450 CYP11B2
Corticosterone
Aldosterone
18-Hydroxycorticosterone
Steroid 11-beta-Hydroxylase
Desoxycorticosterone
Mutation
Hydroxylation
Mixed Function Oxygenases
Genes
Cortodoxone
Cytochrome P-450 Enzyme System
Isoenzymes
Molecular Biology
Cultured Cells
Oxidoreductases
Complementary DNA
Enzymes
Serum

ASJC Scopus subject areas

  • Genetics
  • General

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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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 89, No. 11, 1992, p. 4996-5000.

Research output: Contribution to journalArticle

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