CYP11B1 MUTATIONS CAUSING CONGENITAL ADRENAL-HYPERPLASIA DUE TO 11-BETA-HYDROXYLASE DEFICIENCY

Accurate knowledge of the molecular basis of congenital adrenal hyperp lasia due to 11 beta-hydroxylase deficiency is a prerequisite for gene tic counseling, prenatal diagnosis, and treatment. Analysis of nine pa tients suffering from severe manifestations of this disorder led to th e identification of seven novel. mutations in their CYP11B1 genes. A C aucasian patient was homozygous for the missense mutation R448H, previ ously found only in Jews of Moroccan origin. An Iranian patient was fo und to be homozygous for a different mutation in the same codon, R448C . Of four unrelated patients, two were homozygous for a nonsense mutat ion (W247X), whereas two others were compound heterozygotes for W247X in combination with either R448H or E371G. Two other patients were hom ozygous for either the missense mutation A331V or an in-frame CTG inse rtion adjacent to codon 464 (InsCTG464). One patient was a compound he terozygote for two mutations in exon 2, a 28-bp deletion (Delta 28bpEx 2) and the missense mutation V129M. All of the missense mutations and the CTG insertion caused a complete loss of steroid 11 beta-hydroxylat ing activity when expressed in cultured cells. These data support prev ious suggestions of mutational hot spots in CYP11B1 and confirm that s evere clinical manifestations are associated with complete loss of enz ymatic activity.