Objective: Familial hyperaldosteronism type II (FH-II) is characterized by inheritance of primary aldosteronism (PAL) but, unlike FH-I, is not glucocorticoid remediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. Analysis of two pedigrees previously demonstrated linkage of FH-II with a locus at chromosome 7p22. We sought to determine whether mutations in the exons or intron/exon boundaries in PRKAR1B (encoding protein kinase A regulatory subunit R1-beta), which resides within the linked locus, are associated with FH-II.
Methods: Primers enabling sequencing of all exons and intron/exon boundaries were designed by BLAT search using known mRNA sequence, and comparison with an orthologous mouse gene. Sequences from four affected and two unaffected subjects from an Australian family with FH-II demonstrating linkage at 7p22 were compared with published sequences.
Results: A probable two-nucleotide GenBank sequence error, resulting in an amino acid change, was detected. Two of seven single nucleotide polymorphisms (SNPs) identified were in exons and five in introns. Neither exon-localized SNP resulted in an amino acid change. All intron-localized SNPs were at least 16 nucleotides from the closest intron/exon boundary and therefore unlikely to interfere with gene splicing. Importantly, none of the identified SNPs was exclusively associated with affectation status.
Conclusions: Mutations in the exons or intron/exon boundaries of PRKAR1B do not appear to be responsible for FH-II in this family, but a mutation in the promoter or remaining intronic or 5' or 3' untranslated regions could be. Alternatively, a mutation within another gene residing at the 7p22 locus may be responsible.