BACKGROUND: Deficiency of 11 beta-hydroxylase results in the impairment of the last step of cortisol synthesis. In females, the phenotype of this disorder includes different degrees of genital ambiguity and arterial hypertension. Mutations in the CYP11B1 gene are responsible for this disease. OBJECTIVE: The objective of the study was to screen the CYP11B1 gene for mutations in two unrelated Brazilian females with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. DESIGN: The coding and intron-exon junction regions of CYP11B1 were totally sequenced. A putative splice mutation was further investigated by minigene transcription. RESULTS: We report two novel CYP11B1 mutations in these Brazilian patients. An Arabian Lebanese descendent female was found to be homozygous for a cytosine insertion at the beginning of exon 8, changing the 404 arginine to proline. It alters the open reading frame, creating a putative truncated protein at 421 residue, which eliminates the domain necessary for the association of heme prosthetic group. A severely virilized female was homozygous for the g.2791G>A transition in the last position of exon 4. This nucleotide is also part of 5' intron 4 donor splice site consensus sequence. Minigene experiments demonstrated that g.2791G>A activated an alternative splice site within exon 4, leading to a 45-bp deletion in the transcript. The putative translation of such modified mRNA indicates a truncated protein at residue 280. CONCLUSIONS: We describe two novel mutations, g.4671_4672insC and g.2791G>A, that drastically affects normal protein structure. These mutations abolish normal enzyme activity, leading to a severe phenotype of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.
BACKGROUND: Deficiency of 11 beta-hydroxylase results in the impairment of the last step of cortisol synthesis. In females, the phenotype of this disorder includes different degrees of genital ambiguity and arterial hypertension. Mutations in the CYP11B1 gene are responsible for this disease. OBJECTIVE: The objective of the study was to screen the CYP11B1 gene for mutations in two unrelated Brazilian females with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. DESIGN: The coding and intron-exon junction regions of CYP11B1 were totally sequenced. A putative splice mutation was further investigated by minigene transcription. RESULTS: We report two novel CYP11B1 mutations in these Brazilian patients. An Arabian Lebanese descendent female was found to be homozygous for a cytosine insertion at the beginning of exon 8, changing the 404 arginine to proline. It alters the open reading frame, creating a putative truncated protein at 421 residue, which eliminates the domain necessary for the association of heme prosthetic group. A severely virilized female was homozygous for the g.2791G>A transition in the last position of exon 4. This nucleotide is also part of 5' intron 4 donor splice site consensus sequence. Minigene experiments demonstrated that g.2791G>A activated an alternative splice site within exon 4, leading to a 45-bp deletion in the transcript. The putative translation of such modified mRNA indicates a truncated protein at residue 280. CONCLUSIONS: We describe two novel mutations, g.4671_4672insC and g.2791G>A, that drastically affects normal protein structure. These mutations abolish normal enzyme activity, leading to a severe phenotype of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.
Authors: Audrey Mary Matallana-Rhoades; Juan David Corredor-Castro; Francisco Javier Bonilla-Escobar; Bony Valentina Mecias-Cruz; Liliana Mejia de Beldjena Journal: Colomb Med (Cali) Date: 2016-09-30
Authors: Ahmed Khattab; Shozeb Haider; Ameet Kumar; Samarth Dhawan; Dauood Alam; Raquel Romero; James Burns; Di Li; Jessica Estatico; Simran Rahi; Saleel Fatima; Ali Alzahrani; Mona Hafez; Noha Musa; Maryam Razzghy Azar; Najoua Khaloul; Moez Gribaa; Ali Saad; Ilhem Ben Charfeddine; Berenice Bilharinho de Mendonça; Alicia Belgorosky; Katja Dumic; Miroslav Dumic; Javier Aisenberg; Nurgun Kandemir; Ayfer Alikasifoglu; Alev Ozon; Nazli Gonc; Tina Cheng; Ursula Kuhnle-Krahl; Marco Cappa; Paul-Martin Holterhus; Munier A Nour; Daniele Pacaud; Assaf Holtzman; Sun Li; Mone Zaidi; Tony Yuen; Maria I New Journal: Proc Natl Acad Sci U S A Date: 2017-02-22 Impact factor: 11.205
Authors: Katja Dumic; Tony Yuen; Zorana Grubic; Vesna Kusec; Ingeborg Barisic; Maria I New Journal: Int J Endocrinol Date: 2014-06-02 Impact factor: 3.257
Authors: Silvia Parajes; Lourdes Loidi; Nicole Reisch; Vivek Dhir; Ian T Rose; Rainer Hampel; Marcus Quinkler; Gerard S Conway; Lidia Castro-Feijóo; David Araujo-Vilar; Manuel Pombo; Fernando Dominguez; Emma L Williams; Trevor R Cole; Jeremy M Kirk; Elke Kaminsky; Gill Rumsby; Wiebke Arlt; Nils Krone Journal: J Clin Endocrinol Metab Date: 2010-01-20 Impact factor: 5.958