Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

Ute I. Scholl, Gabriel Stölting, Carol Nelson-Williams, Alfred A. Vichot, Murim Choi, Erin Loring, Manju L. Prasad, Gerald Goh, Tobias Carling, C. Christofer Juhlin, Ivo Quack, Lars C. Rump, Anne Thiel, Marc Lande, Britney G. Frazier, Majid Rasoulpour, David L. Bowlin, Christine B. Sethna, Howard Trachtman, Christoph FahlkeRichard P. Lifton

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135 Scopus citations


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 CACNA1H(M1549V) 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. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

Original languageEnglish
Article numbere06315
Pages (from-to)e06315
StatePublished - 24 Apr 2015


  • CaV3.2
  • adrenal gland
  • chromosomes
  • de novo mutation
  • exome sequencing
  • genes
  • human
  • human biology
  • incomplete penetrance
  • medicine
  • voltage-gated calcium channel

Cite this

Scholl, U. I., Stölting, G., Nelson-Williams, C., Vichot, A. A., Choi, M., Loring, E., Prasad, M. L., Goh, G., Carling, T., Juhlin, C. C., Quack, I., Rump, L. C., Thiel, A., Lande, M., Frazier, B. G., Rasoulpour, M., Bowlin, D. L., Sethna, C. B., Trachtman, H., ... Lifton, R. P. (2015). Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. eLife, 4, e06315. [e06315].