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Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis.

Authors
 Jessica LaRusch  ;  Jinsei Jung  ;  Ignacio J. General  ;  Michele D. Lewis  ;  Hyun Woo Park  ;  Randall E. Brand  ;  Andres Gelrud  ;  Michelle A. Anderson  ;  Peter A. Banks  ;  Darwin Conwell  ;  Christopher Lawrence  ;  Joseph Romagnuolo  ;  John Baillie  ;  Samer Alkaade  ;  Gregory Cote  ;  Timothy B. Gardner  ;  Stephen T. Amann  ;  Adam Slivka  ;  Bimaljit Sandhu  ;  Amy Aloe  ;  Michelle L. Kienholz  ;  Dhiraj Yadav  ;  M. Michael Barmada  ;  Ivet Bahar  ;  Min Goo Lee  ;  David C. Whitcomb 
Citation
 PLoS Genetics, Vol.10(7) : e1004376, 2014 
Journal Title
 PLoS Genetics 
ISSN
 1553-7390 
Issue Date
2014
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.
Files in This Item:
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DOI
10.1371/journal.pgen.1004376
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
박현우(Park, Hyun Woo)
이민구(Lee, Min Goo) ORCID logo https://orcid.org/0000-0001-7436-012X
정진세(Jung, Jinsei) ORCID logo https://orcid.org/0000-0003-1906-6969
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/99249
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