Steroid 11-beta-hydroxylase deficiency caused by compound heterozygosity for a novel mutation, p.G314R, in one CYP11B1 allele, and a chimeric CYP11B2/CYP11B1 in the other allele

Isao Kuribayashi, Satoshi Nomoto, Guy Massa, Wilma Oostdijk, Jan M. Wit, Bruce H R Wolffenbuttel, Yutaka Shizuta, Koichi Honke

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Aims: Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common (5-8%) cause of congenital adrenal hyperplasia (CAH), and results from homozygous or compound heterozygous mutations or deletions of the responsible gene CYP11B1. In order to better understand the molecular basis causing 11β-OHD, we performed detailed studies of CYP11B1 in a newly described patient diagnosed with the classical signs of 11β-OHD. Methods: CYP11B1 of the patient was investigated by polymerase chain reaction (PCR), sequencing, restriction fragment length polymorphism (RFLP) analysis. Southern blotting, and transient cell expression. Results: We identified two new mutated alleles in CYP11B1. In one allele CYP11B1 has a g.940G→C (p.G314R) missense mutation. On the other allele we found a chimeric gene that consists of part of the aldosterone synthase gene (CYP11B2) at exons 1-3 and part of the 11β-hydroxylase gene (CYP11B1) at exons 4-9. In in vitro studies, the g.940G→C (p.G314R) mutation abolished all hydroxylase activity in comparison with the wild-type 11β-hydroxylase. The chimeric CYP11B2/CYP11B1 protein retained 11β-hydroxylase enzymatic activity in vitro. Conclusion: This case is caused by compound heterozygosity for a nonfunctional missense mutation and a chimeric CYP11B2/CYP11B1 gene with hydroxylase activity that is controlled by the CYP11B2 promoter. The most likely explanation is that the CYP11B2 promoter does not function in the zona fasciculata/reticularis where cortisol is exclusively synthesized.

Original languageEnglish
Pages (from-to)284-292
Number of pages9
JournalHormone Research
Volume63
Issue number6
DOIs
Publication statusPublished - Aug 2005
Externally publishedYes

Fingerprint

Steroid 11-beta-Hydroxylase
Cytochrome P-450 CYP11B2
Alleles
Mutation
Mixed Function Oxygenases
Missense Mutation
Genes
Exons
Zona Reticularis
Zona Fasciculata
Congenital adrenal hyperplasia due to 11-Beta-hydroxylase deficiency
Congenital Adrenal Hyperplasia
Sequence Deletion
Gene Deletion
Southern Blotting
Restriction Fragment Length Polymorphisms
Hydrocortisone

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Steroid 11-beta-hydroxylase deficiency caused by compound heterozygosity for a novel mutation, p.G314R, in one CYP11B1 allele, and a chimeric CYP11B2/CYP11B1 in the other allele. / Kuribayashi, Isao; Nomoto, Satoshi; Massa, Guy; Oostdijk, Wilma; Wit, Jan M.; Wolffenbuttel, Bruce H R; Shizuta, Yutaka; Honke, Koichi.

In: Hormone Research, Vol. 63, No. 6, 08.2005, p. 284-292.

Research output: Contribution to journalArticle

Kuribayashi, Isao ; Nomoto, Satoshi ; Massa, Guy ; Oostdijk, Wilma ; Wit, Jan M. ; Wolffenbuttel, Bruce H R ; Shizuta, Yutaka ; Honke, Koichi. / Steroid 11-beta-hydroxylase deficiency caused by compound heterozygosity for a novel mutation, p.G314R, in one CYP11B1 allele, and a chimeric CYP11B2/CYP11B1 in the other allele. In: Hormone Research. 2005 ; Vol. 63, No. 6. pp. 284-292.
@article{925d7c50fde64b78b738db68ab128890,
title = "Steroid 11-beta-hydroxylase deficiency caused by compound heterozygosity for a novel mutation, p.G314R, in one CYP11B1 allele, and a chimeric CYP11B2/CYP11B1 in the other allele",
abstract = "Aims: Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common (5-8{\%}) cause of congenital adrenal hyperplasia (CAH), and results from homozygous or compound heterozygous mutations or deletions of the responsible gene CYP11B1. In order to better understand the molecular basis causing 11β-OHD, we performed detailed studies of CYP11B1 in a newly described patient diagnosed with the classical signs of 11β-OHD. Methods: CYP11B1 of the patient was investigated by polymerase chain reaction (PCR), sequencing, restriction fragment length polymorphism (RFLP) analysis. Southern blotting, and transient cell expression. Results: We identified two new mutated alleles in CYP11B1. In one allele CYP11B1 has a g.940G→C (p.G314R) missense mutation. On the other allele we found a chimeric gene that consists of part of the aldosterone synthase gene (CYP11B2) at exons 1-3 and part of the 11β-hydroxylase gene (CYP11B1) at exons 4-9. In in vitro studies, the g.940G→C (p.G314R) mutation abolished all hydroxylase activity in comparison with the wild-type 11β-hydroxylase. The chimeric CYP11B2/CYP11B1 protein retained 11β-hydroxylase enzymatic activity in vitro. Conclusion: This case is caused by compound heterozygosity for a nonfunctional missense mutation and a chimeric CYP11B2/CYP11B1 gene with hydroxylase activity that is controlled by the CYP11B2 promoter. The most likely explanation is that the CYP11B2 promoter does not function in the zona fasciculata/reticularis where cortisol is exclusively synthesized.",
author = "Isao Kuribayashi and Satoshi Nomoto and Guy Massa and Wilma Oostdijk and Wit, {Jan M.} and Wolffenbuttel, {Bruce H R} and Yutaka Shizuta and Koichi Honke",
year = "2005",
month = "8",
doi = "10.1159/000087074",
language = "English",
volume = "63",
pages = "284--292",
journal = "Hormone Research in Paediatrics",
issn = "1663-2818",
publisher = "S. Karger AG",
number = "6",

}

TY - JOUR

T1 - Steroid 11-beta-hydroxylase deficiency caused by compound heterozygosity for a novel mutation, p.G314R, in one CYP11B1 allele, and a chimeric CYP11B2/CYP11B1 in the other allele

AU - Kuribayashi, Isao

AU - Nomoto, Satoshi

AU - Massa, Guy

AU - Oostdijk, Wilma

AU - Wit, Jan M.

AU - Wolffenbuttel, Bruce H R

AU - Shizuta, Yutaka

AU - Honke, Koichi

PY - 2005/8

Y1 - 2005/8

N2 - Aims: Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common (5-8%) cause of congenital adrenal hyperplasia (CAH), and results from homozygous or compound heterozygous mutations or deletions of the responsible gene CYP11B1. In order to better understand the molecular basis causing 11β-OHD, we performed detailed studies of CYP11B1 in a newly described patient diagnosed with the classical signs of 11β-OHD. Methods: CYP11B1 of the patient was investigated by polymerase chain reaction (PCR), sequencing, restriction fragment length polymorphism (RFLP) analysis. Southern blotting, and transient cell expression. Results: We identified two new mutated alleles in CYP11B1. In one allele CYP11B1 has a g.940G→C (p.G314R) missense mutation. On the other allele we found a chimeric gene that consists of part of the aldosterone synthase gene (CYP11B2) at exons 1-3 and part of the 11β-hydroxylase gene (CYP11B1) at exons 4-9. In in vitro studies, the g.940G→C (p.G314R) mutation abolished all hydroxylase activity in comparison with the wild-type 11β-hydroxylase. The chimeric CYP11B2/CYP11B1 protein retained 11β-hydroxylase enzymatic activity in vitro. Conclusion: This case is caused by compound heterozygosity for a nonfunctional missense mutation and a chimeric CYP11B2/CYP11B1 gene with hydroxylase activity that is controlled by the CYP11B2 promoter. The most likely explanation is that the CYP11B2 promoter does not function in the zona fasciculata/reticularis where cortisol is exclusively synthesized.

AB - Aims: Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common (5-8%) cause of congenital adrenal hyperplasia (CAH), and results from homozygous or compound heterozygous mutations or deletions of the responsible gene CYP11B1. In order to better understand the molecular basis causing 11β-OHD, we performed detailed studies of CYP11B1 in a newly described patient diagnosed with the classical signs of 11β-OHD. Methods: CYP11B1 of the patient was investigated by polymerase chain reaction (PCR), sequencing, restriction fragment length polymorphism (RFLP) analysis. Southern blotting, and transient cell expression. Results: We identified two new mutated alleles in CYP11B1. In one allele CYP11B1 has a g.940G→C (p.G314R) missense mutation. On the other allele we found a chimeric gene that consists of part of the aldosterone synthase gene (CYP11B2) at exons 1-3 and part of the 11β-hydroxylase gene (CYP11B1) at exons 4-9. In in vitro studies, the g.940G→C (p.G314R) mutation abolished all hydroxylase activity in comparison with the wild-type 11β-hydroxylase. The chimeric CYP11B2/CYP11B1 protein retained 11β-hydroxylase enzymatic activity in vitro. Conclusion: This case is caused by compound heterozygosity for a nonfunctional missense mutation and a chimeric CYP11B2/CYP11B1 gene with hydroxylase activity that is controlled by the CYP11B2 promoter. The most likely explanation is that the CYP11B2 promoter does not function in the zona fasciculata/reticularis where cortisol is exclusively synthesized.

UR - http://www.scopus.com/inward/record.url?scp=23844466570&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23844466570&partnerID=8YFLogxK

U2 - 10.1159/000087074

DO - 10.1159/000087074

M3 - Article

C2 - 16024935

AN - SCOPUS:23844466570

VL - 63

SP - 284

EP - 292

JO - Hormone Research in Paediatrics

JF - Hormone Research in Paediatrics

SN - 1663-2818

IS - 6

ER -