title: Genetic characterization of a mouse line with primary aldosteronism.
abstract: In an attempt to define novel genetic loci involved in the pathophysiology of primary aldosteronism, a mutagenesis screen after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. One of the generated mouse lines with hyperaldosteronism was phenotypically and genetically characterized. This mouse line had high aldosterone levels but normal creatinine and urea values. The steroidogenic enzyme expression levels in the adrenal gland did not differ significantly among phenotypically affected and unaffected mice. Upon exome sequencing, point mutations were identified in seven candidate genes (Sspo, Dguok, Hoxaas2, Clstn3, Atm, Tipin and Mapk6). Subsequently, animals were stratified into wild-type and mutated groups according to their genotype for each of these candidate genes. A correlation of their genotypes with the respective aldosterone, aldosterone-to-renin ratio (ARR), urea and creatinine values as well as steroidogenic enzyme expression levels was performed. Aldosterone values were significantly higher in animals carrying mutations in four different genes (Sspo, Dguok, Hoxaas2 and Clstn3) and associated statistically significant adrenal Cyp11b2 overexpression as well as increased ARR was present only in mice with Sspo mutation. In contrast, mutations of the remaining candidate genes (Atm, Tipin and Mapk6) were associated with lower aldosterone values and lower Hsd3b6 expression levels. In summary, these data demonstrate association between the genes Sspo, Dguok, Hoxaas2 and Clstn3 and hyperaldosteronism. Final proofs for the causative nature of the mutations have to come from knock-out and knock-in experiments.
authors.affiliation: Medizinische Klinik und Poliklinik IVEndocrine Research Unit, Klinikum der Universität München, LMU, Munich, Germany.
authors.forename: L G
authors.initials: LG
authors.lastname: Perez-Rivas
authors.affiliation: Medizinische Klinik und Poliklinik IVEndocrine Research Unit, Klinikum der Universität München, LMU, Munich, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Rhayem
authors.affiliation: Helmholtz Zentrum MünchenGerman Research Center for Environmental Health (GmbH), Institute of Experimental Genetics and German Mouse Clinic, Neuherberg, Germany.|Helmholtz Zentrum MünchenGerman Research Center for Environmental Health (GmbH), Research Unit Comparative Medicine, Neuherberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sabrautzki
authors.affiliation: Medizinische Klinik und Poliklinik IVEndocrine Research Unit, Klinikum der Universität München, LMU, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Hantel
authors.affiliation: Helmholtz Zentrum MünchenGerman Research Center for Environmental Health (GmbH), Institute of Experimental Genetics and German Mouse Clinic, Neuherberg, Germany.|Member of German Center for Diabetes Research (DZD)Neuherberg, Germany.|Ludwig-Maximilians-Universität MünchenChair for Molecular Animal Breeding and Biotechnology, Gene Center of the München, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Rathkolb
authors.affiliation: Helmholtz Zentrum MünchenGerman Research Center for Environmental Health (GmbH), Institute of Experimental Genetics and German Mouse Clinic, Neuherberg, Germany.|Member of German Center for Diabetes Research (DZD)Neuherberg, Germany.|Lehrstuhl für Experimentelle GenetikTechnische Universität München, Freising-Weihenstephan, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: Medizinische Klinik und Poliklinik IVEndocrine Research Unit, Klinikum der Universität München, LMU, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Reincke
authors.affiliation: Medizinische Klinik und Poliklinik IVEndocrine Research Unit, Klinikum der Universität München, LMU, Munich, Germany felix.beuschlein@med.uni-muenchen.de.
authors.forename: F
authors.initials: F
authors.lastname: Beuschlein
authors.affiliation: Medizinische Klinik und Poliklinik IVEndocrine Research Unit, Klinikum der Universität München, LMU, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Spyroglou
mesh_terms: D000450:Aldosterone / Q000097:blood / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006929:Hyperaldosteronism / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D015415:Biomarkers; D000450:Aldosterone
keywords: mouse model; mutagenesis screen; primary aldosteronism; steroidogenic enzymes