CYP11B1 mutations causing congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.

Accurate knowledge of the molecular basis of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is a prerequisite for genetic counseling, prenatal diagnosis, and treatment. Analysis of nine patients suffering from severe manifestations of this disorder led to the identification of seven novel mutations in their CYP11B1 genes. A Caucasian patient was homozygous for the missense mutation R448H, previously found only in Jews of Moroccan origin. An Iranian patient was found to be homozygous for a different mutation in the same codon, R448C. Of four unrelated patients, two were homozygous for a nonsense mutation (W247X), whereas two others were compound heterozygotes for W247X in combination with either R448H or E371G. Two other patients were homozygous for either the missense mutation A331V or an in-frame CTG insertion adjacent to codon 464 (InsCTG464). One patient was a compound heterozygote for two mutations in exon 2, a 28-bp deletion (delta 28bpEx2) and the missense mutation V129M. All of the missense mutations and the CTG insertion caused a complete loss of steroid 11 beta-hydroxylating activity when expressed in cultured cells. These data support previous suggestions of mutational hot spots in CYP11B1 and confirm that severe clinical manifestations are associated with complete loss of enzymatic activity.