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Mutations in CYP11B1 Gene Converting 11ß-Hydroxylase into an Aldosterone-Producing Enzyme Are Not Present in Aldosterone-Producing Adenomas

Department of Medical and Surgical Sciences, Division of Endocrinology (C.P, L.B., M.B., N.S., F.F.), University of Padova, 35128 Padova; and the Department of Medicine and Experimental Oncology (P.M., F.V.) and the Division of Surgery (C.G.), University of Torino, 10133 Torino, Italy

Address all correspondence and requests for reprints to: Francesco Fallo, M.D., Department of Medical and Surgical Sciences, Division of Endocrinology, Via Ospedale 105, 35128 Padova, Italy.

In the human adrenal cortex, cortisol and aldosterone are synthesized by the isozymes 11ß-hydroxylase and aldosterone synthase, respectively, encoded by the 93% identical CYP11B1 and CYP11B2 genes. In vitro mutagenesis of CYP11B1 complementary DNA, resulting in the replacement of CYP11B1 codons by those encoding the corresponding amino acid residues of CYP11B2 enzyme (exon 5, Ser²⁸⁸Gly; exon 6, Val³²⁰Ala), yields a complementary DNA encoding a mutant enzyme with an efficient aldosterone synthase activity. Identical somatic mutations in the CYP11B1 gene in vivo would produce a gene encoding an enzyme with C₁₈ activity and that would preserve ACTH responsiveness due to the retained 5'-promoter in the mutated CYP11B1 gene. An ACTH-responsive aldosterone synthase activity of this type is commonly seen in patients with aldosterone-producing adenomas (APA). We examined the occurrence of mutations in exons 5 and 6 of the CYP11B1 gene in APA from 10 patients with primary aldosteronism. Patients were selected on preoperative evidence of a 50% or greater plasma aldosterone decrease after short term dexamethasone trial and no aldosterone response to upright posture. DNA from adenomas was amplified by PCR using two pairs of primers spanning the regions of CYP11B1 gene, i.e. exons 3–5 and exons 6–9, where mutations could be located. Targeted regions were screened for mutations by automated sequencing of PCR products. No point mutations of the CYP11B1 gene over the two regions examined were found in APA. This argues against involvement of mutations in the pathogenesis of ACTH-responsive APA.

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