Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
18307725
TITLE
Examination of chromosome 7p22 candidate genes RBaK, PMS2 and GNA12 in familial hyperaldosteronism type II.
ABSTRACT
1. There are two types of familial hyperaldosteronism (FH): FH-I and FH-II. FH-I is caused by a hybrid CYP11B1/CYP11B2 gene mutation. The genetic cause of FH-II, which is more common, is unknown. Adrenal hyperplasia and adenomas are features. We previously reported linkage of FH-II to a approximately 5 Mb region on chromosome 7p22. We subsequently reported finding no causative mutations in the retinoblastoma-associated Kruppel-associated box gene (RBaK), a candidate at 7p22 involved in tumorigenesis and cell cycle control. 2. In the current study we investigated RBaK regulatory regions and two other candidate genes: postmeiotic segregation increased 2 (PMS2, involved in DNA mismatch repair and tumour predisposition) and guanine nucleotide-binding protein alpha-12 (GNA12, a transforming oncogene). 3. The GNA12 and PMS2 genes were examined in two affected (A1, A2) and two unaffected (U1, U2) subjects from a large 7p22-linked FH-II family (family 1). No mutations were found. 4. The RBaK and PMS2 distal promoters were sequenced to -2150 bp from the transcription start site for RBaK and-2800 bp for PMS2. Five unreported single nucleotide polymorphisms (SNPs) were found in subjects A1, A2 but not in U1 or U2; A(-2031 bp)T, T(-2030 bp)G, G(-834 bp)C, C(-821 bp)G in RBaK and A(-876 bp)G in PMS2. Additional affected and unaffected subjects from family 1 and from two other 7p22-linked FH-II families and 58 unrelated normotensive control subjects were genotyped for these SNPs. 5. The five novel SNPs were found to be present in a significant proportion of normotensive controls. The four RBaK promoter SNPs were found to be in linkage disequilibrium in the normal population. The RBaK promoter (-)2031T/2030G/834C/821T allele was found to be in linkage disequilibrium with the causative mutation in FH-II family 1, but not in families 2 and 3. The PMS2 promoter (-)876G allele was also found to be linked to affected phenotypes in family 1. 6. The RBaK and PMS2 promoter SNPs alter the binding sites for several transcription factors. Although present in the normal population, it is possible that the RBaK (-)2031T/2030G/834C/821T and PMS2 (-)876G alleles may have functional roles contributing to the FH-II phenotype in family 1.
DATE PUBLISHED
2008 Apr
HISTORY
PUBSTATUS PUBSTATUSDATE
pubmed 2008/03/01 09:00
medline 2008/05/23 09:00
entrez 2008/03/01 09:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Jeske YW Jeske Y W A YW Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes Hospital, Brisbane, Queensland, Australia. y.jeske@uq.edu.au
So A So A A
Kelemen L Kelemen L L
Sukor N Sukor N N
Willys C Willys C C
Bulmer B Bulmer B B
Gordon RD Gordon R D RD
Duffy D Duffy D D
Stowasser M Stowasser M M
INVESTIGATORS
JOURNAL
VOLUME: 35
ISSUE: 4
TITLE: Clinical and experimental pharmacology & physiology
ISOABBREVIATION: Clin. Exp. Pharmacol. Physiol.
YEAR: 2008
MONTH: Apr
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1440-1681
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Clin Exp Pharmacol Physiol
COUNTRY: Australia
ISSNLINKING: 0305-1870
NLMUNIQUEID: 0425076
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
5' Untranslated Regions genetics
Adenosine Triphosphatases genetics
Adult genetics
Aged genetics
Chromosomes, Human, Pair 7 genetics
DNA Repair Enzymes genetics
DNA-Binding Proteins genetics
Female genetics
Genetic Markers genetics
Genetic Predisposition to Disease genetics
Humans genetics
Hyperaldosteronism genetics
Intracellular Signaling Peptides and Proteins genetics
Male genetics
Middle Aged genetics
Polymorphism, Single Nucleotide genetics
Promoter Regions, Genetic genetics
RNA Splice Sites genetics
Repressor Proteins genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 5' Untranslated Regions
0 DNA-Binding Proteins
0 Genetic Markers
0 Intracellular Signaling Peptides and Proteins
0 RBaK protein, human
0 RNA Splice Sites
0 Repressor Proteins
0 URI1 protein, human
EC 3.6.1.- Adenosine Triphosphatases
EC 3.6.1.- PMS2 protein, human
EC 6.5.1.- DNA Repair Enzymes
OTHER ID's