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

LaRusch, J and Jung, J and General, IJ and Lewis, MD and Park, HW and Brand, RE and Gelrud, A and Anderson, MA and Banks, PA and Conwell, D and Lawrence, C and Romagnuolo, J and Baillie, J and Alkaade, S and Cote, G and Gardner, TB and Amann, ST and Slivka, A and Sandhu, B and Aloe, A and Kienholz, ML and Yadav, D and Barmada, MM and Bahar, I and Lee, MG and Whitcomb, DC (2014) Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis. PLoS Genetics, 10 (7). ISSN 1553-7390

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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. © 2014 Whitcomb et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
LaRusch, J
Jung, J
General, IJijgenera@pitt.eduIJGENERA
Lewis, MD
Park, HW
Brand, REreb53@pitt.eduREB53
Gelrud, A
Anderson, MA
Banks, PA
Conwell, D
Lawrence, C
Romagnuolo, J
Baillie, J
Alkaade, S
Cote, G
Gardner, TB
Amann, ST
Slivka, Aaslivka@pitt.eduASLIVKA
Sandhu, B
Aloe, A
Kienholz, MLmlk39@pitt.eduMLK39
Yadav, Ddhy2@pitt.eduDHY2
Barmada, MMbarmada@pitt.eduBARMADA
Bahar, Ibahar@pitt.eduBAHAR
Lee, MG
Whitcomb, DCwhitcomb@pitt.eduWHITCOMB
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorMcCarty, NaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 January 2014
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 10
Number: 7
DOI or Unique Handle: 10.1371/journal.pgen.1004376
Schools and Programs: Graduate School of Public Health > Human Genetics
School of Medicine > Cell Biology and Molecular Physiology
School of Medicine > Computational and Systems Biology
School of Medicine > Medicine
Refereed: Yes
ISSN: 1553-7390
Date Deposited: 23 Sep 2014 15:57
Last Modified: 02 Feb 2019 16:58
URI: http://d-scholarship.pitt.edu/id/eprint/23015

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