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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Aldosterone / biosynthesis
  • Aldosterone / metabolism
  • Amino Acid Sequence
  • Calcium / metabolism*
  • Calcium Channels, T-Type / genetics*
  • Calcium Channels, T-Type / metabolism
  • Calcium Signaling
  • Child
  • Child, Preschool
  • Female
  • Gene Expression
  • Genotype
  • Heterozygote
  • Humans
  • Hyperaldosteronism / complications
  • Hyperaldosteronism / genetics*
  • Hyperaldosteronism / metabolism
  • Hyperaldosteronism / pathology
  • Hypertension / complications
  • Hypertension / genetics*
  • Hypertension / metabolism
  • Hypertension / pathology
  • Infant
  • Male
  • Membrane Potentials
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Phenotype
  • Recurrence
  • Sequence Alignment
  • Zona Glomerulosa / metabolism
  • Zona Glomerulosa / pathology

Substances

  • CACNA1H protein, human
  • Calcium Channels, T-Type
  • Aldosterone
  • Calcium