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. About 40% of these tumors are caused by mutations in the potassium channel KCNJ5 (Choi et al. Science 2011), about 10% by mutations in the voltage-gated calcium channel CACNA1D (Scholl et al. Nature Genetics 2013), and about 7% 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). By electrophysiology, this mutation causes reduced channel inactivation and activation at less depolarized potentials. Lastly, we recently demonstrated that mutations in the gene CLCN2 similarly cause familial hyperaldosteronism (Scholl et al. Nature Genetics 2018). This gene encodes a chloride channel whose activation leads to the depolarization of aldosterone-producing cells. Its role in adrenal gland function had been completely unknown. In current projects, we investigate families without mutations in the known hyperaldosteronism genes and aim to better understand the development, regulation and function of the adrenal cortex.
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.
In collaborative projects, we aim to identify genetic causes of different diseases, including those of the nervous system
Dr. med. vet. Julia Schewe
Dr. med. Gabriel Stölting
Dipl.-Chem. Eric Seidel
Monique Karge, M.Sc. (starting 08/15/2018)
Dipl.-Ing. (FH) Nicole Hellmig
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
Reimer EN, Walenda G, Seidel E, Scholl UI. CACNA1HM1549V mutant calcium channel causes autonomous aldosterone production in HAC15 cells and is inhibited by Mibefradil. Endocrinology 2016;157:3016-22
Thiel A, Reis AC, Haase M, Goh G, Schott M, Willenberg HS, Scholl UI. PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases. Eur J Endocrinol 2015;172:677-685
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
Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloglu A, Ozen S, Sanjad S, Nelson-Williams C, Farhi A, Mane S, Lifton RP. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci USA 2009;106:19096-19101
Scholl UI, Choi M, Liu T, Ramaekers VT, Hausler MG, Grimmer J, Tobe SW, Farhi A, Nelson-Williams C, Lifton RP. Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc Natl Acad Sci USA 2009;106:5842-5847
Janssen AG, Scholl U, Domeyer C, Nothmann D, Leinenweber A, Fahlke C. Disease-causing dysfunctions of barttin in Bartter syndrome type IV. J Am Soc Nephrol 2009;20:145-153
Scholl U, Hebeisen S, Janssen AG, Müller-Newen G, Alekov A, Fahlke C. Barttin modulates trafficking and function of ClC-K channels. Proc Natl Acad Sci USA 2006;103:11411-11416