CLCN2 chloride channel mutations in familial hyperaldosteronism type II


  • U.I. Scholl
  • G. Stölting
  • J. Schewe
  • A. Thiel
  • H. Tan
  • C. Nelson-Williams
  • A.A. Vichot
  • S.C. Jin
  • E. Loring
  • V. Untiet
  • T. Yoo
  • J. Choi
  • S. Xu
  • A. Wu
  • M. Kirchner
  • P. Mertins
  • L.C. Rump
  • A.M. Onder
  • C. Gamble
  • D. McKenney
  • R.W. Lash
  • D.P. Jones
  • G. Chune
  • P. Gagliardi
  • M. Choi
  • R. Gordon
  • M. Stowasser
  • C. Fahlke
  • R.P. Lifton


  • Nature Genetics


  • Nat Genet 50 (3): 349-354


  • 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.