Center of Genomic Medicine

Hypertension and Molecular Biology of Endocrine Tumors

Ute Scholl

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.

Management:

Univ.-Prof. Dr. med. Ute Scholl

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

Phone:: +49 30 450 543 080
E-mail:: ute.scholl[at]charite.de
Address:: Berliner Institut für Gesundheitsforschung in der Charité – Universitätsmedizin Berlin
Hessische Straße 4A
10115 Berlin

Research focus

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 2013, Azizan 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 2011, Scholl 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.

Selected publications
Seidel E, Schewe J, Zhang J, Dinh HA, Forslund SK, Markó L, Hellmig N, Peters J, Muller DN, Lifton RP, Nottoli T, Stölting G, Scholl UI. Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+). Proc Natl Acad Sci USA 2021;118:e2014876118
Schewe J, Seidel E, Forslund S, Marko L, Peters J, Muller DN, Fahlke C, Stölting G, Scholl U. Elevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC-2 mutation. Nat Commun 2019 10:5155. doi: 10.1038/s41467-019-13033-4.
Scholl UI, Stölting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, Vichot AA, Jin SC, Loring E, Untiet V, Yoo T, Choi J, Xu S, Wu A, Kirchner M, Mertins P, Rump LC, Onder AM, Gamble C, McKenney D, Lash RW, Jones DP, Chune G, Gagliardi P, Choi M, Gordon R, Stowasser M, Fahlke C, Lifton RP. CLCN2 Chloride Channel Mutations in Familial Hyperaldosteronism Type II. Nat Genet 2018; 2018; 50:349-354
Scholl UI, Abriola L, Zhang C, Reimer EN, Plummer M, Kazmierczak BI, Zhang J, Hoyer D, Merkel JS, Wang W, Lifton RP*. Macrolides selectively inhibit mutant KCNJ5 channels that cause aldosterone-producing adenomas. J Clin Invest 2017; 127:2739-2750
Scholl UI, Stölting G, Nelson-Williams C, Vichot AA, Choi M, Loring E, Prasad ML, Goh G, Carling T, Juhlin CC, Quack I, Rump LC, Thiel A, Lande M, Frazier BG, Rasoulpour M, Bowlin DL, Sethna CB, Trachtman H, Fahlke C, Lifton RP. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. Elife 2015;4:e06315
Goh G, Scholl UI, Healy JM, Choi M, Prasad ML, Nelson-Williams C, Kunstman JW, Korah R, Suttorp AC, Dietrich D, Haase M, Willenberg HS, Stalberg P, Hellman P, Akerstrom G, Bjorklund P, Carling T, Lifton RP. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat Genet 2014;46:613-617
Scholl UI, Goh G, Stölting G, de Oliveira RC, Choi M, Overton JD, Fonseca AL, Korah R, Starker LF, Kunstman JW, Prasad ML, Hartung EA, Mauras N, Benson MR, Brady T, Shapiro JR, Loring E, Nelson-Williams C, Libutti SK, Mane S, Hellman P, Westin G, Akerstrom G, Bjorklund P, Carling T, Fahlke C, Hidalgo P, Lifton RP. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 2013;45:1050-1054
Scholl UI, Nelson-Williams C, Yue P, Grekin R, Wyatt RJ, Dillon MJ, Couch R, Hammer LK, Harley FL, Farhi A, Wang WH, Lifton RP. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc Natl Acad Sci USA 2012;109:2533-2538
Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Akerstrom G, Wang W, Carling T, Lifton RP. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011;331:768-772

Funding
Deutsche Forschungsgemeinschaft
- Collaborative Research Center “Renoprotection”
- Collaborative Research Center “Nephrogenetics”
- Research Unit “SLC26 Integrated analysis of epithelial SLC26 anion transporters - from molecular structure to pathophysiology”
Stiftung Charité