2. Academic Validation
  3. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

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

  • Elife. 2015 Apr 24;4:e06315. doi: 10.7554/eLife.06315.
Ute I Scholl 1,  Gabriel Stölting 2,  Carol Nelson-Williams 1,  Alfred A Vichot 1,  Murim Choi 1,  Erin Loring 1,  Manju L Prasad 3,  Gerald Goh 1,  Tobias Carling 4,  C Christofer Juhlin 4,  Ivo Quack 5,  Lars C Rump 5,  Anne Thiel 5,  Marc Lande 6,  Britney G Frazier 7,  Majid Rasoulpour 8,  David L Bowlin 9,  Christine B Sethna 10,  Howard Trachtman 11,  Christoph Fahlke 2,  Richard P Lifton 1
Affiliations

Affiliations

  • 1 Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
  • 2 Institute of Complex Systems, Zelluläre Biophysik, Forschungszentrum Jülich, Jülich, Germany.
  • 3 Department of Pathology, Yale University School of Medicine, New Haven, United States.
  • 4 Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, United States.
  • 5 Division of Nephrology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 6 Division of Pediatric Nephrology, University of Rochester Medical Center, Rochester, United States.
  • 7 Madigan Army Medical Center, Tacoma, United States.
  • 8 Connecticut Children's Medical Center, Hartford, United States.
  • 9 Intermed Consultants Ltd, Edina, United States.
  • 10 Department of Pediatrics, Cohen Children's Medical Center of New York, New Hyde Park, United States.
  • 11 Department of Pediatrics, NYU Langone Medical Center, New York, United States.
PMID: 25907736 DOI: 10.7554/eLife.06315
Abstract

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.

Keywords

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

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