FURTHER EVIDENCE OF LINKAGE AT 7P22 WITH FAMILIAL HYPERALDOSTERONISM TYPE II (FH-II) AND EXAMINATION OF THE RBAK CODING REGIONS

摘要

Background: Once thought rare, primary aldosteronism (PAL) is now reported to be responsible for 5-10% of hypertension. Unlike familial hyperaldosteronism type I (FH-I), FH-II is not glucocorticoid-remediable and not associated with the hybrid CYP11BJ/CYP11B2 gene mutation. At least five times more common than FH-I, FH-II is clinically indistinguishable from apparently sporadic PAL, suggesting an even higher incidence. Studies performed in collaboration with C Stratakis (NIH, Bethesda) on our largest Australian family (eight affected members) demonstrated linkage at chromosome 7p22. Linkage at this region was also found in a South American family (0NA provided by MI New, Mount Sinai School of Medicine, New York) and in a second Australian family. The combined multipoint LOD score for these 3 families is 4.61 (0 = 0) with markers D7S462 and D7S517, providing strong support for this locus harbouring mutations responsible for FH-II. A newly identified recombination event in our largest Australian family has narrowed the region of linkage by 1.8 Mb, permitting exclusion of approximately half the genes residing in the originally reported 5 Mb linked locus. Candidate genes that are involved in cell cycle control are of interest as adrenal hyperplasia and adrenal adenomas are common in FH-II patients. A novel candidate gene in this linked region produces the retinoblastoma-associated Kruppel-associated box protein (RBaK) which interacts with the retinoblastoma gene product to repress the expression of genes activated by members of the E2F family of transcription factors.