CLCN2 chloride channel mutations in familial hyperaldosteronism type II

Nat Genet. 2018 Mar;50(3):349-354. doi: 10.1038/s41588-018-0048-5. Epub 2018 Feb 5.

Abstract

Primary aldosteronism, a common cause of severe hypertension 1 , features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II) 2 and 80 additional probands with unsolved early-onset primary aldosteronism. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of a mutation encoding an identical p.Arg172Gln substitution; all relatives with early-onset primary aldosteronism carried the CLCN2 variant found in the proband. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Mutant channels show gain of function, with higher open probabilities at the glomerulosa resting potential. These findings for the first time demonstrate a role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. They establish the cause of a substantial fraction of early-onset primary aldosteronism.

Publication types

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

MeSH terms

  • Adolescent
  • Adrenal Glands / metabolism
  • Adrenal Glands / pathology
  • Adult
  • Amino Acid Sequence
  • Child
  • Chloride Channels / genetics*
  • Cohort Studies
  • DNA Mutational Analysis
  • Female
  • Humans
  • Hyperaldosteronism / genetics*
  • Hyperaldosteronism / pathology
  • Infant
  • Male
  • Mutation*
  • Pedigree
  • Young Adult

Substances

  • Chloride Channels
  • ClC-2 chloride channels

Supplementary concepts

  • Familial Hyperaldosteronism