Reporter: Aviva Lev-Ari, PhD, RN
Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension
- Felix Beuschlein,
- Sheerazed Boulkroun,
- Andrea Osswald,
- Thomas Wieland,
- Hang N Nielsen,
- Urs D Lichtenauer,
- David Penton,
- Vivien R Schack,
- Laurence Amar,
- Evelyn Fischer,
- Anett Walther,
- Philipp Tauber,
- Thomas Schwarzmayr,
- Susanne Diener,
- Elisabeth Graf,
- Bruno Allolio,
- Benoit Samson-Couterie,
- Arndt Benecke,
- Marcus Quinkler,
- Francesco Fallo,
- Pierre-Francois Plouin,
- Franco Mantero,
- Thomas Meitinger,
- Paolo Mulatero,
- Xavier Jeunemaitre,
- Richard Warth,
- Bente Vilsen,
- Maria-Christina Zennaro,
- Tim M Strom
- & Martin Reincke
- Published online 17 February 2013
- Mutations affecting a pair of related enzyme-coding genes can contribute to the
risk of benign glandular tumors
- called adenomas and secondary hypertension, a new
- study suggests. An international team led by investigators in Germany performed
- on matched tumor and normal samples from nine individuals with forms of adenoma that enhance aldosterone hormone production. This leads to a type of so-called aldosteronism that can bump up blood pressure and cause other adverse symptoms.
When researchers sorted through the exome sequence data, they saw ties between aldosterone-producing adenoma and mutations in two ATPase genes — ATP1A1 and ATP2B3 — that participate in sodium/potassium and calcium signaling, respectively. Somatic ATP1A1 mutations turned up in more than 5 percent of 308 aldosterone-producing adenoma samples screened subsequently, the team noted, while 1.6 percent of those tumors contained ATP2B3 alterations.
“[T]hese findings expand the spectrum of somatic alterations leading to [aldosterone-producing adenomas] to two members of the P-type ATPase pump family, extend knowledge of the molecular mechanism leading to [aldosterone-producing adenoma],” the Ludwig Maximilian University of Munich researcher Martin Reincke, the study’s corresponding author, and colleagues wrote, “and indicate new potential therapeutic targets for the most frequent secondary form of arterial hypertension.”
SOURCE:
http://www.genomeweb.com//node/1194476?hq_e=el&hq_m=1505701&hq_l=6&hq_v=6fcaf1aef4
Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension
Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na+/K+ ATPase α subunit) and ATP2B3 (encoding a Ca2+ ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3.
Mutation-positive cases showed
- male dominance,
- increased plasma aldosterone concentrations and
- lower potassium concentrations compared with mutation-negative cases.
In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.
Author information
SOURCE:
http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2550.html
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