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Deletion Hybrid Genes, due to Unequal Crossing Over between CYP11B1 (11ß-Hydroxylase) and CYP11B2(Aldosterone Synthase) Cause Steroid 11ß-Hydroxylase Deficiency and Congenital Adrenal Hyperplasia¹

INSERM, U-342, Laboratoire de Biochimie Endocrinienne, Hopital Debrousse (S.P., Y.M.), 69322 Lyon, France; Hypertension Unit, University of Torino (P.M.), 10132 Torino, Italy; Baker Medical Research Institute (K.M.C.), Prahran 3181, Australia; Pediatric Endocrinology, Hopital Saint Vincent de Paul (J.-L.C.), 75674 Paris, France; and Fondation Jean Dausset CEPH (L.P.), 75010 Paris, France

Address all correspondence and requests for reprints to: Dr. Leigh Pascoe, Fondation Jean Dausset CEPH, 27 rue Juliette Dodu, 75010 Paris, France. E-mail: leigh{at}cephb.fr

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 11ß-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 11ß-hydroxylase and aldosterone synthase activities. Apparently the 11ß-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.

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