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 11β-hydroxylase (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.


OBJECTIVE
To report an unprecedented case of a de novo unequal crossover mutation between CYP11B1 and CYP11B2 genes causing FH-I.


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. XLPCR 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.


CONCLUSIONS
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.
Carvajal
C A
CA
Endocrinology Department, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile.
Stehr
C B
CB
González
P A
PA
Riquelme
E M
EM
Montero
T
T
Santos
M J
MJ
Kalergis
A M
AM
Fardella
C E
CE
D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D003434:Crossing Over, Genetic; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D006929:Hyperaldosteronism / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics*
D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase