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Elife. 2015 Apr 24;4:e06315. doi: 10.7554/eLife.06315.

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

Author information

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.

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

PMID:
25907736
PMCID:
PMC4408447
DOI:
10.7554/eLife.06315
[Indexed for MEDLINE]
Free PMC Article

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