Soardi, Fernanda C.
Penachioni, Junia Y.
Justo, Giselle Z.
Bachega, Tania A. S. S.
Mendonca, Berenice B.
de Castro, Margaret
de Mello, Maricilda P.
 Univ Fed Sao Paulo, Dept Bioquim, Disciplina Biol Mol, BR-04023900 Sao Paulo - Brazil
 Univ Sao Paulo, Unidade Endocrinol Desenvolvimento Disciplina End, Lab Invest Med 42, Lab Hormonios & Genet Mol, Hosp Clin, Fac Med, BR-05403900 Sao Paulo - Brazil
 Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Clin Med, BR-05508090 Ribeirao Preto - Brazil
Total Affiliations: 4
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM;
Web of Science Citations:
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. (J Clin Endocrinol Metab 94: 3481-3485, 2009) (AU)