MUTATION T318M IN THE CYPIIB2 GENE ENCODING P450CIIAS (ALDOSTERONE SYNTHASE) CAUSES CORTICOSTERONE METHYL OXIDASE-II DEFICIENCY

Corticosterone methyl oxidase (CMO) deficiency refers to disorders of aldosterone synthesis due to mutations in the CYP11B2 gene encoding cy tochrome P450c11AS, which is the adrenal aldosterone synthase. Type I CMO deficiency is associated with low concentrations of 18OH-corticost erone and aldosterone, due to severe mutations in P450c11AS; while typ e II CMO deficiency is associated with high concentrations of 18OH-cor ticosterone and low concentrations of aldosterone, due to less severe mutations of P450c11AS. A single type of mutation, compound homozygosi ty for R181W and V386A, has been reported as the cause of CMOII defici ency in an inbred population. We now report a patient with a typical c linical and hormonal picture of CMOII deficiency. Direct sequencing of patient and parent DNAs showed that the mother's allele contributed R 181W and the deletion/frameshift mutation Delta C372, while the father 's allele contributed T3318M and V386A. These mutants were recreated i n cDNA expression vectors singly and in the parental pairs, showing th at neither allele contributed any measurable activity. This would sugg est the patient should have CMOI deficiency. These studies suggest tha t other factors besides P450c11AS are involved in the genesis of the d istinctive CMOI and CMOII phenotypes.