Frame shift by insertion of 2 basepairs in codon 394 of CYP11B1 causes congenital adrenal hyperplasia due to steroid 11 beta-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of corticosteroid biosynthesis primarily caused by a deficiency in either of two heme-containing cytochrome P450-enzymes: steroid 21- or 11 beta-hydroxylase (causing approximately 90% and 5-8% of classical CAH cases, respectively). Depending on the patient's gender, the affected enzyme, and the extent of enzymatic dysfunction, symptoms include adrenal hyperplasia, androgen excess, virilization, growth disturbance, and electrolyte imbalance. To define the molecular basis of steroid 11 beta-hydroxylase-deficient CAH, we cloned and sequenced the CYP11B1 gene (encoding 11 beta-hydroxylase) of a female patient afflicted with this disorder. Exon 7 contained a 2-basepair insertion in codon 394, leading to a reading frame shift, multiple incorrect codons, and a premature stop in codon 469, resulting in complete destruction of the enzyme's heme-binding domain. Due to parental consanguinity, this defect was homozygous and, therefore, provides a full molecular explanation for this disease.