title: Deletion hybrid genes, due to unequal crossing over between CYP11B1 (11beta-hydroxylase) and CYP11B2(aldosterone synthase) cause steroid 11beta-hydroxylase deficiency and congenital adrenal hyperplasia.
abstract: Chromosomal rearrangements are natural experiments that can provide unique insights into in vivo regulation of genes and physiological systems. We have studied a patient with congenital adrenal hyperplasia and steroid 11beta-hydroxylase deficiency who was homozygous for a deletion of the CYP11B1 and CYP11B2 genes normally required for cortisol and aldosterone synthesis, respectively. The genes were deleted by unequal recombination between the tandemly arranged CYP11B genes during a previous meiosis, leaving a single hybrid gene consisting of the promoter and exons 1-6 of CYP11B2 and exons 7-9 of CYP11B1. The hybrid gene also carried an I339T mutation formed by intracodon recombination at the chromosomal breakpoint. The mutant complementary DNA corresponding to this gene was expressed in COS-1 cells and was found to have relatively unimpaired 11beta-hydroxylase and aldosterone synthase activities. Apparently the 11beta-hydroxylase deficiency and the adrenal hyperplasia are due to the lack of expression of this gene in the adrenal zona fasciculata/reticularis resulting from replacement of the CYP11B1 promoter and regulatory sequences by those of CYP11B2.
authors.affiliation: INSERM, U-342, Laboratoire de Biochimie Endocrinienne, Hopital Debrousse, 69322 Lyon, France.
authors.forename: S
authors.initials: S
authors.lastname: Portrat
authors.forename: P
authors.initials: P
authors.lastname: Mulatero
authors.forename: K M
authors.initials: KM
authors.lastname: Curnow
authors.forename: J L
authors.initials: JL
authors.lastname: Chaussain
authors.forename: Y
authors.initials: Y
authors.lastname: Morel
authors.forename: L
authors.initials: L
authors.lastname: Pascoe
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D000450:Aldosterone / Q000097:blood; D000735:Androstenedione / Q000097:blood; D000818:Animals; D015139:Blotting, Southern; D019556:COS Cells; D002675:Child, Preschool; D003350:Cortodoxone / Q000097:blood; D003434:Crossing Over, Genetic; D017373:Cyproterone Acetate / Q000627:therapeutic use; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons; D017353:Gene Deletion; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011629:Puberty, Precocious / Q000188:drug therapy / Q000235:genetics; D012083:Renin / Q000097:blood; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics*; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D000735:Androstenedione; D000450:Aldosterone; D017373:Cyproterone Acetate; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D012083:Renin; D003350:Cortodoxone