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Hypertension affects more than one billion people worldwide. As the leading risk factor for global disease burden, it contributes to more than nine million deaths annually. The mission of the Scholl group is the discovery and characterization of novel mechanisms underlying human disease. We focus on genetic causes of childhood hypertension and hypertension caused by hormone-producing tumors. We combine state-of-the-art genomics technology (exome capture and next-generation sequencing; single-cell RNA sequencing) with mainstay techniques of genetics, molecular biology, cell biology, biochemistry and physiology (electrophysiology, calcium imaging) to identify and characterize new genes and networks in human biology. A long-term goal is to develop pharmacological inhibitors that interfere with these processes to improve future therapy.

Mutations in patients with primary aldosteronism

Patients with primary aldosteronism (Conn syndrome) show elevated levels of the blood pressure hormone aldosterone. About 6% of patients with hypertension have primary aldosteronism. The most common causes include aldosterone-producing adenomas (benign hormone-producing tumors of the adrenal gland) and bilateral adrenal hyperplasia, a condition that features increased hormone production from both glands.

Over the past few years, exome sequencing studies have identified tumor-specific (somatic) mutations in ion channels and transporters as frequent causes of aldosterone-producing adenomas (Seidel et al. Exp Mol Med 2019). About 40% of these tumors are caused by mutations in the potassium channel KCNJ5 (Choi et al. Science 2011), about 20% by mutations in the voltage-gated calcium channel CACNA1D (Scholl et al. Nature Genetics 2013), and about 20% by mutations in the Na+/K+-ATPase subunit ATP1A1 or the plasma membrane calcium ATPase ATP2B3 (Beuschlein et al. Nature Genetics 2013Azizan et al. Nature Genetics 2013).

KCNJ5 mutations cause abnormal sodium permeability of the channel, with subsequent depolarization and activation of voltage-gated calcium channels. The resulting calcium influx is the signal for aldosterone production and proliferation. CACNA1D mutations directly cause increased calcium influx, whereas the mechanism of ATPase mutations appears to be sodium or hydrogen ion permeability and depolarization similar to the pathophysiology of KCNJ5 mutations.

The same or related KCNJ5 mutations as in tumors were identified in the germline of patients with familial hyperaldosteronism (Choi et al. Science 2011Scholl et al. PNAS 2012). Germline mutations in the CACNA1D gene were found in two patients with a new syndrome of primary aldosteronism, seizures and neurologic abnormalities (PASNA, Scholl et al. Nature Genetics 2013). We also reported a recurrent germline mutation in the voltage-gated calcium channel CACNA1H in patients with early-onset primary aldosteronism (Scholl et al. eLIFE 2015, Seidel et al. PNAS 2021). By electrophysiology, this mutation causes reduced channel inactivation and activation at less depolarized potentials. Lastly, we demonstrated that mutations in the gene CLCN2 similarly cause familial hyperaldosteronism (Scholl et al. Nature Genetics 2018, Schewe et al. Nature Communications 2019). This gene encodes a chloride channel whose activation leads to the depolarization of aldosterone-producing cells.

In current projects, we recruit and investigate families without mutations in the known hyperaldosteronism genes and aim to better understand the development, regulation and function of the adrenal cortex. We generate and characterize cellular and animal models of primary aldosteronism.

Mutations in other hormone-producing tumors

We are studying additional hormone-producing tumors from various parts of the body to identify known or novel disease-causing mutations and better understand their pathophysiology.

Pharmacology of adrenal disease

We could show that macrolides, which are clinically used as antibiotics, specifically inhibit mutant KCNJ5 channels (Scholl et al. Journal of Clinical Investigation 2017). This effect is independent of their antibiotic activity, and we hope to further optimize these compounds for diagnostic and therapeutic use, using structural biology and rational design.

Akkordeon

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Management:

Univ.-Prof. Dr. med. Ute Scholl

BIH Johanna Quandt Professor for Hypertension and Molecular Biology of Endocrine Tumors

Contact information
Address:Berliner Institut für Gesundheitsforschung in der Charité – Universitätsmedizin Berlin
Hessische Straße 4A

10115 Berlin

Postdocs:

PhD students:

Student Assistants:

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Technical assistant:

Dipl.-Ing. (FH) Nicole Hellmig

Contact information
E-mail:nicole.hellmig@bih-charite.de