Amino acid substitution R384P in aldosterone synthase causes corticosterone methyloxidase type I deficiency.
Corticosterone methyloxidase type I (CMO-I) deficiency is an autosomal recessively inherited disorder causing congenital hypoaldosteronism due to defects in aldosterone synthase (P450aldo), the enzyme that converts 11-deoxycorticosterone to corticosterone, 18-hydroxycorticosterone, and aldosterone. To clarify the molecular basis of CMO-I deficiency and gain further insight into the structure-function relationship of P450aldo, we cloned and sequenced the CYP11B2 gene (encoding P450aldo) of a male Caucasian patient suffering from CMO-I deficiency and identified a single point mutation leading to substitution of the highly conserved arginine-384 by proline (R384P). Differential hybridization of mutation-specific oligonucleotide probes to polymerase chain reaction-amplified CYP11B2 fragments revealed that both parents were heterozygous carriers for R384P, whereas the patient appeared homozygous. The patient's healthy brother and 85 individuals without known aldosterone synthase deficiency did not carry the R384P mutation. Introduction of this mutation into a CYP11B2 complementary DNA expression vector construct and subsequent expression in COS cells revealed that R384P leads to complete loss of 11 beta- and 18-hydroxylase activities of P450aldo. Thus, the R384P mutation provides a molecular explanation for the CMO-I deficiency in this patient and suggests that arginine-384 plays a major role in P450aldo function.