Genetics of primary aldosteronism - familial hyperaldosteronism type II

So, Albertina (2007). Genetics of primary aldosteronism - familial hyperaldosteronism type II PhD Thesis, School of Medicine, University of Queensland.

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Author So, Albertina
Thesis Title Genetics of primary aldosteronism - familial hyperaldosteronism type II
School, Centre or Institute School of Medicine
Institution University of Queensland
Publication date 2007
Thesis type PhD Thesis
Supervisor Michael Stowasser
Total pages 243
Language eng
Subjects 11 Medical and Health Sciences
Abstract/Summary BACKGROUND: Primary aldosteronism (PAL), caused by autonomous overproduction of aldosterone by the adrenals, is the commonest curable and specifically treatable cause of hypertension. There are two familial varieties. Familial hyperaldosteronism type I (FH-I) is glucocorticoid suppressible and caused by a CYP11B1/CYP11B2 "hybrid" gene mutation. Familial hyperaldosteronism type II (FH-II), which appears to be at least five times more common, is not attributable to the "hybrid" gene mutation and not glucocorticoid suppressible. FH-II is clinically, biochemically and morphologically indistinguishable from apparently sporadic PAL, which could therefore have a similar genetic basis. Since diagnosing PAL by currently available biochemical methods is difficult, finding a simple and reliable genetic test for FH-II which could also be applied to apparently sporadic PAL would simplify patient management. A genome-wide search performed previously had demonstrated linkage of FH-II to chromosome 7p22, consistent with this locus harbouring the causative gene/s for FH-II. AIM: The overall aim of this thesis was to elucidate the genetic basis of FH-II and thereby permit development of new genetic tests which will streamline the identification of individuals predisposed to developing of PAL. In order to achieve this overall aim, the specific aims of the thesis were to narrow the linked region at 7p22 by phenotyping and genotyping more FH-II families using markers more closely spaced than those utilized previously, and by sequencing candidate genes in the narrowed linked region for FH-II associated mutations. METHOD AND RESULTS: As a prelude to the FH-II studies, examination of a large FH-I family with 21 genetically-confirmed affecteds by linkage analysis showed that linkage results were markedly affected by phenotypic variability and decisions regarding affectation status criteria. This highlighted the need for careful consideration of these factors to enable location of significant linkage. Initially, five FH-II families (96 subjects) were carefully phenotyped and then genotyped using seven closely spaced 7p22 microsatellite markers. These studies confirmed linkage at 7p22 in a large Australian family and a South American family previously studied in the SupervisorsÂ’ laboratory and, in addition, revealed linkage at 7p22 in a second Australian family (combined LOD score 4.61 for the three families). Recombination events in two affecteds in the largest studied Australian family narrowed the linkage region by at least 1.8 Mbp and halved the number of candidate genes. Absence of linkage at 7p22 in two other Australian families was also demonstrated, consistent with FH-II being genetically heterogeneous. Subsequent microsatellite studies using seven additional 7p22 markers examining the three 7p22-linked families resulted in a further reduction of the linked locus by 0.5 Mbp. Two candidate genes in this linked region were then examined for mutations causing FH-II; the retinoblastoma-associated Kruppel-associated box gene (RBaK) and postmeiotic segregation increased 2 (PMS2) were selected as they are involved in cell cycle control and adrenal hyperplasia and adenomas are common in FH-II. Coding regions and intron/exon splice sites were sequenced in affected and unaffected subjects from a 7p22-linked FH-II family. Identified single nucleotide polymorphisms (SNPs) were genotyped to assess significance. For RBaK, the T allele of a synonymous 2565C>T SNP was shared by all 15 affecteds from the three 7p22-linked families, but was also common in 16 unaffecteds (28%), seven affecteds from two 7p22 non-linked families (50%) and 20 non-PAL normotensive controls (43%), and is therefore unlikely to be causative. No other polymorphisms were found. For PMS2, 11 SNPs were found [two in the proximal promoter: -195T/C and -154C/G; four non-synonymous coding SNPs: C1408T (P470S), C1454A (T485K), A1531G (T511A) and G1621A (E541K); two synonymous coding SNPs: C288T and G780C; two in splice sites: 2006+6G/A and 2007-4G/A; one in an intronic region: 705+17 A/G]. These 11 SNPs were genotyped in 14 affecteds from the three 7p22-linked families, and in 14 non-PAL controls. None showed segregation of alleles with disease status. CONCLUSION: Work from this thesis has confirmed linkage of FH-II to chromosome 7p22 in three of five FH-II families examined. Recombination events in two affecteds from one family resulted in a substantial narrowing of the area of linkage and halving of the number of candidate genes needing to be investigated for association with FH-II. The finding that the gene responsible for FH-II might be located at 7p22 is supported by a recent report from the Framingham Heart Study showing genetic linkage of the aldosterone/renin ratio to the 7p region. Examination of two candidate genes (RBaK and PMS2) so far has shown no evidence of mutations causing FH-II.
Keyword Hyperaldosteronism

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Created: Fri, 21 Nov 2008, 16:13:16 EST