Dokument: Investigations of somatic and germline mutations in primary aldosteronism

Titel:	Investigations of somatic and germline mutations in primary aldosteronism
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=44787
URN (NBN):	urn:nbn:de:hbz:061-20180202-094259-0
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Reimer, Esther [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 3,52 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 02.02.2018 / geändert 02.02.2018
Beitragende:	Prof. Dr. Scholl, Ute [Gutachter] Prof. Dr. Fahlke, Christoph [Gutachter]
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:	Primary hyperaldosteronism (PHA) is a subform of secondary hypertension. It can be caused e. g. by bilateral adrenal hyperplasia or aldosterone-producing adenomas (APAs). Recurrent somatic mutations in the genes KCNJ5, CACNA1D, ATP1A1, ATP1A2 and CTNNB1 have been identified in APAs and have been characterized to varying extent. One study in this work matches the mutational status of APAs to patient and tumor characteristics. KCNJ5 was the most frequently mutated gene in our cohort (37.1%), resulting in larger tumors with zona fasciculata-like appearance, which presented less dense in CT scans. Patients with KCNJ5 mutated APAs were more often female, while male predominance was observed for the other mutations. The frequency for other known mutations was: CACNA1D (10.3%), ATP1A2 (8.2%), ATP2B3 (3.1%) and CTNNB1 (2.1%) There is a general consensus that KCNJ5 is the most frequently mutated gene in APAs, with G151R and L168R alterations accounting for almost all cases. According to the second study included in this work, macrolides can block KCNJ5 G151R and L168R channels without affecting the wild type. Roxithromycin, the most promising macrolide in the study, is able to reduce both aldosterone production and aldosterone synthase (CYP11B2) expression in adrenocortical cells expressing mutant KCNJ5. The non-antibiotic macrolide PLUX 38 similarly reduced CYP11B2 expres-sion. In the future, blockers of mutant KCNJ5 channels might present an option in the diagnosis and treatment of patients with KCNJ5 mutant APAs. Familial forms of PHA have been traced back to alterations in the CYP11B2 gene as well as to mutations in KCNJ5, CACNA1D and CACNA1H, while sometimes the underlying causes remain unknown. The third study in this work substantiates the role of the germline CACNA1H M1549V mutation as a cause of familial hyperaldosteronism type IV (FH IV). The variant was first discovered in patients with early-onset PHA and electrophysiological studies suggested a gain of function of the mutant channel. Our investigations show that aldosterone production and CYP11B2 expression is increased in adrenocortical cells transfected with mutant CACNA1H compared to the wild type. This effect can be reduced or even abrogated by the T-type calcium channel blocker mibefradil. Notably, cells carrying CACNA1H M1549V still respond to normal stimuli of aldosterone production, i. e. angiotensin II and increased extracellular K+. Another mutation studied in this work is CACNA1H S1073C, which was identified in monozygotic twins with PHA and their family members. Transfection of adrenocortical cells with CACNA1H S1073C did not result in differences in CYP11B2 expression or aldosterone production compared to the wild type, suggesting that the mutation is not disease-causing. The studies in this work enhance our understanding of the underlying mechanisms of PHA, confirming the role of the CACNA1H M1549V mutation in FH IV and linking APA mutations to a specific phenotype. They provide new impulses for diagnosis and treatment of PHA, especially through the identification of macrolides as blockers of mutant KCNJ5 channels. Nevertheless, sometimes, the underlying genetics of PHA remain unclear, as in the case of the patients with a CACNA1H S1073C mutation.
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie
Dokument erstellt am:	02.02.2018
Dateien geändert am:	02.02.2018
Promotionsantrag am:	11.10.2017
Datum der Promotion:	29.01.2018