TY - JOUR TI - Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism AU - Scholl, Ute I AU - Stölting, Gabriel AU - Nelson-Williams, Carol AU - Vichot, Alfred A AU - Choi, Murim AU - Loring, Erin AU - Prasad, Manju L AU - Goh, Gerald AU - Carling, Tobias AU - Juhlin, C Christofer AU - Quack, Ivo AU - Rump, Lars C AU - Thiel, Anne AU - Lande, Marc AU - Frazier, Britney G AU - Rasoulpour, Majid AU - Bowlin, David L AU - Sethna, Christine B AU - Trachtman, Howard AU - Fahlke, Christoph AU - Lifton, Richard P A2 - Ginsburg, David VL - 4 PY - 2015 DA - 2015/04/24 SP - e06315 C1 - eLife 2015;4:e06315 DO - 10.7554/eLife.06315 UR - https://doi.org/10.7554/eLife.06315 AB - Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1HM1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension. KW - adrenal gland KW - CaV3.2 KW - voltage-gated calcium channel KW - exome sequencing KW - incomplete penetrance KW - de novo mutation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -