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PLoS Genet. 2014 Jul 17;10(7):e1004376. doi: 10.1371/journal.pgen.1004376. eCollection 2014.

Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis.

Author information

  • 1Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
  • 2Department of Pharmacology and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
  • 3Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
  • 4Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, United States of America.
  • 5Department of Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
  • 6Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
  • 7Digestive Disease Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
  • 8Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
  • 9Department of Internal Medicine, St. Louis University School of Medicine, St Louis, Missouri, United States of America.
  • 10Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
  • 11Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, United States of America.
  • 12North Mississippi Medical Center, Tupelo, Mississippi, United States of America.
  • 13Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center, Richmond, Virginia, United States of America.
  • 14Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
  • 15Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

Erratum in

  • PLoS Genet. 2014 Oct;10(10):e1004778.

Abstract

CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway-activated increases in CFTR bicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.

PMID:
25033378
PMCID:
PMC4102440
DOI:
10.1371/journal.pgen.1004376
[PubMed - indexed for MEDLINE]
Free PMC Article
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