Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7, and 8

Kathleen M. Curnow, Liliya Slutsker, Jiri Vitek, Trevor Cole, Phyllis W. Speiser, Maria I. New, Perrin C. White, Leigh Pascoe

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Abstract

Steroid 11β-hydroxylase deficiency (failure to convert 11-deoxycortisol to cortisol) is the second most common cause of congenital adrenal hyperplasia and results in a hypertensive form of the disease. The 11β-hydroxylase enzyme is encoded by the CYP11B1 gene on chromosome 8q22. Two mutations in CYP11B1 have previously been reported in patients with 11β-hydroxylase deficiency - Arg-448 → His and a 2-bp insertion in codon 394. We now report eight previously uncharacterized mutations causing this disorder. Seven are point mutations (three nonsense and four missense) and one is a single base pair deletion causing a frameshift. We have used an in vitro transfection assay to show that all five known missense mutations causing 11β-hydroxylase deficiency abolish enzymatic activity. In principle, deletions of CYP11B1 could be generated by unequal crossing-over between CYP11B1 and the adjacent CYP11B2 gene, but no such deletions were found among the deficiency alleles in this study. Seven of the 10 known mutations are clustered in exons 6-8, a nonrandom distribution within the gene. This may reflect the location of functionally important amino acid residues within the enzyme or an increased tendency to develop mutations within this region of the gene.

Original languageEnglish (US)
Pages (from-to)4552-4556
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number10
StatePublished - May 15 1993

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Steroid 11-beta-Hydroxylase
Congenital Adrenal Hyperplasia
Exons
Hypertension
Mixed Function Oxygenases
Mutation
Genes
Cytochrome P-450 CYP11B2
Cortodoxone
Missense Mutation
Enzymes
Point Mutation
Codon
Base Pairing
Transfection
Hydrocortisone
Chromosomes
Alleles
Amino Acids

ASJC Scopus subject areas

  • General
  • Genetics

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Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7, and 8. / Curnow, Kathleen M.; Slutsker, Liliya; Vitek, Jiri; Cole, Trevor; Speiser, Phyllis W.; New, Maria I.; White, Perrin C.; Pascoe, Leigh.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 90, No. 10, 15.05.1993, p. 4552-4556.

Research output: Contribution to journalArticle

Curnow, Kathleen M. ; Slutsker, Liliya ; Vitek, Jiri ; Cole, Trevor ; Speiser, Phyllis W. ; New, Maria I. ; White, Perrin C. ; Pascoe, Leigh. / Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7, and 8. In: Proceedings of the National Academy of Sciences of the United States of America. 1993 ; Vol. 90, No. 10. pp. 4552-4556.
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N2 - Steroid 11β-hydroxylase deficiency (failure to convert 11-deoxycortisol to cortisol) is the second most common cause of congenital adrenal hyperplasia and results in a hypertensive form of the disease. The 11β-hydroxylase enzyme is encoded by the CYP11B1 gene on chromosome 8q22. Two mutations in CYP11B1 have previously been reported in patients with 11β-hydroxylase deficiency - Arg-448 → His and a 2-bp insertion in codon 394. We now report eight previously uncharacterized mutations causing this disorder. Seven are point mutations (three nonsense and four missense) and one is a single base pair deletion causing a frameshift. We have used an in vitro transfection assay to show that all five known missense mutations causing 11β-hydroxylase deficiency abolish enzymatic activity. In principle, deletions of CYP11B1 could be generated by unequal crossing-over between CYP11B1 and the adjacent CYP11B2 gene, but no such deletions were found among the deficiency alleles in this study. Seven of the 10 known mutations are clustered in exons 6-8, a nonrandom distribution within the gene. This may reflect the location of functionally important amino acid residues within the enzyme or an increased tendency to develop mutations within this region of the gene.

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