A de novo unequal cross-over mutation between CYP11B1 and CYP11B2 genes causes familial hyperaldosteronism type I

Familial hyperaldosteronism type I (FH-I) is an autosomal dominant disorder caused by an unequal cross-over of the gene encoding steroid 11βhydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), giving rise to a chimeric CYP11B1/CYP11B2 gene that displays aldosterone synthase activity regulated by ACTH instead of angiotensin II. Aim: To report an unprecedented case of a de novo unequal cross-over mutation between CYP11B1 and CYP11B2 genes causing FH-I. Patients and methods: The index case is a 45-yr-old Chilean male diagnosed with primary aldosteronism (PA). All family members were also studied: his biological parents, 1 brother, 6 sisters, 2 daughters, and 1 son. Plasma renin activity, serum aldosterone, and its ratio were measured in all patients. Genetic analyses were performed using long-extension PCR (XL-PCR), DNA sequencing and Southern blot methods. Results: PA was diagnosed for the index case, 1 of his daughters, his son but not for his parents or siblings. XL-PCR and Southern blotting demonstrated the presence of the chimeric CYP11B1/CYP11B2 gene solely in PA-affected subjects, suggesting a case of a de novo mutation. Sequence analysis showed the unequal cross-over CYP11B1/CYP11B2 at intron 2 (c.2600-273 CYP11B2). We also identified a polymorphism at the same intron (c.2600-145C>A CYP11B2) in the genome of the index case's father. Conclusion: We describe an unprecedented case of unequal cross-over mutation for the chimeric CYP11B1/CYP11B2 gene causing FH-I, which may be linked to a polymorphism in the index case's father germ line.