Further study of chromosome 7p22 to identify the molecular basis of familial hyperaldosteronism type II

Abstract

Familial hyperaldosteronism type II (FH-II) is an inherited form of hyperaldosteronism associated with hypertension in most patients. The mutations that cause FH-II are unknown, but linkage analysis has mapped them to chromosome 7p22. As FH-II is clinically indistinguishable from sporadic primary aldosteronism, a common and treatable condition, unravelling the cause of FH-II has important implications for these sporadic cases. To investigate whether FH-II is caused by large deletions or insertions, we examined the virtual karyotype of four pairs of affected and unaffected individuals using highdensity bead chips. We also sequenced the coding regions of five 7p22 candidate genes that were prioritized because of their putative role in cell growth. We found no evidence of single-nucleotide polymorphism (SNP) copy number variation between pairs, and from the widest gap on the chip, chromosome 7p22 deletions or insertions exceeding B50 kb in these pedigrees can be excluded. We found 15 SNPs (two of which were novel), but none of them were non-synonymous and segregated with the disease in the FH-II pedigrees. We have been able to exclude large genomic deletions or insertions at 7p22 and refine the candidate gene list for this locus, but the mutations causing FH-II remain elusive.

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

“…Early candidate gene approaches found no evidence for causative mutations in CYP11B2 (524), CYP11B1 (140), the ANG II type 1 receptor gene (AT1) (525), the p53 tumor suppressor gene (33), or the multiple endocrine neoplasia type 1 gene (MEN1) (524). Although linkage studies employing microsatellite markers appeared to implicate a locus at chromosome 7p22 with a highly significant combined logarithm of odds (LOD) score of 5.29 among 5 families (2 Australian, 2 Italian, and 1 South American) (471,511), an extensive search in this region by both direct Sanger sequencing of multiple candidate genes (76,131,249,472,508) and next generation sequencing of the entire linked locus (unpublished observations) has so far failed to identify causative mutations. Because of this, the search has been widened and results of intensive whole exomic sequencing analyses (including our largest affected family) are awaited with great interest.…”

Genetics and epigenetics of adrenocortical tumors

“…The prevalence of FH-II ranges from ∼1 – 6% (Mulatero, Tauber et al 2012, Pallauf, Schirpenbach et al 2012). The genetic cause is unknown, but linkage analysis of non-related families indicates a locus at chromosome 7p22 (Carss, Stowasser et al 2011). Sequencing candidate genes located in this region, fascin 1 (FSCN1) and the cAMP-dependent protein kinase type I b-regulatory subunit (PRKAR1B) , revealed no mutations (Medeau, Assie et al 2005).…”

cAMP/PKA signaling defects in tumors: Genetics and tissue-specific pluripotential cell-derived lesions in human and mouse

“…Familial hyperaldosteronism type-II (FH-II) is the term that we and others have used to describe familial non-GRA aldosterone-producing BAH that is inherited in an autosomal dominant manner (Torpy et al, 1998; Carss et al, 2011). We have mapped a subset of families with this disorder to chromosome 7p22, a locus that has also been seen in GWA studies of hypertension (Lafferty et al, 2000; Elphinstone et al, 2004).…”