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A Compound Heterozygote Case of Type II Aldosterone Synthase Deficiency

Baker Medical Research Institute (F.M.D., J.W.F., K.M.C.), Melbourne 8008, Victoria, Australia; John Hunter Children’s Hospital, University of Newcastle (P.A.C.), Newcastle 2308, New South Wales, Australia; and Dorevitch Pathology (J.M.), Heidelberg 3084, Victoria, Australia

Address all correspondence and requests for reprints to: Prof. John W. Funder, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail: john.funder{at}med.monash edu.au.

An infant with failure to thrive, persistent hyponatremia and episodic vomiting and diarrhea was admitted to hospital at 9 months of age, and the diagnosis of type II aldosterone synthase deficiency was confirmed by plasma and urinary steroid determinations. The entire coding sequence of the aldosterone synthase gene (CYP11B2) was determined (both strands) in the affected infant, an unaffected sibling, and both parents. An exon 3 mutation (C554T, leading to amino acid T185I) was found in the father and both siblings, and an exon 9 mutation (A1492G, leading to T498A) was found in the affected infant and the mother. Expression of the mutant sequences in COS cells showed steroidogenic patterns typical of aldosterone synthase type II deficiency, including very low levels of aldosterone synthesis (0.5% of wild-type enzyme) consistent with the low aldosterone levels in the patient’s plasma. Both mutations in this compound heterozygote localize to the ß3-sheet in the cytochrome P450 enzyme structure, as does the previously characterized R181W mutation. This region of the enzyme is not part of the putative structural core, but mutations to this region suggest that it is important for conferring the unique ability of aldosterone synthase to catalyze efficient oxygenation of the C₁₈ carbon of steroid substrates.

Present address for F.M.D.: Amrad Corporation Ltd., 576 Swan Street, Richmond, Victoria 3121, Australia.

Present address for J.W.F.: Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia.

Present address for K.M.C.: Pharmacia Australia, 59 Kirby Street, Rydalmere, New South Wales 2116, Australia.

Abbreviations: CMO, Corticosterone methyl oxidase; DOC, 11-deoxycorticosterone; FCS, fetal calf serum; pCMV4, mammalian expression vector driven by a cytomegalovirus promoter; PRA, plasma renin activity; TLC, thin layer chromatography.

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