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Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis
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نویسنده
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larusch j. ,jung j. ,general i.j. ,lewis m.d. ,park h.w. ,brand r.e. ,gelrud a. ,anderson m.a. ,banks p.a. ,conwell d. ,lawrence c. ,romagnuolo j. ,baillie j. ,alkaade s. ,cote g. ,gardner t.b. ,amann s.t. ,slivka a. ,sandhu b. ,aloe a. ,kienholz m.l. ,yadav d. ,barmada m.m. ,bahar i. ,lee m.g. ,whitcomb d.c.
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منبع
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plos genetics - 2014 - دوره : 10 - شماره : 7
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چکیده
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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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آدرس
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department of medicine,division of gastroenterology,hepatology and nutrition,university of pittsburgh,pittsburgh,pa, United States, department of pharmacology and brain korea 21 plus project for medical science,yonsei university college of medicine,seoul, South Korea, department of computational and systems biology,university of pittsburgh,pittsburgh,pa, United States, division of gastroenterology and hepatology,mayo clinic,jacksonville,fl, United States, department of pharmacology and brain korea 21 plus project for medical science,yonsei university college of medicine,seoul,south korea,sanford consortium for regenerative medicine,university of california,san diego,la jolla,ca, United States, department of medicine,division of gastroenterology,hepatology and nutrition,university of pittsburgh,pittsburgh,pa, United States, department of medicine,division of gastroenterology,hepatology and nutrition,university of pittsburgh,pittsburgh,pa,united states,university of chicago,chicago,il, United States, department of medicine,university of michigan,ann arbor,mi, United States, division of gastroenterology,brigham and women's hospital,boston,ma, United States, division of gastroenterology,brigham and women's hospital,boston,ma,united states,the ohio state university,columbus,oh, United States, digestive disease center,medical university of south carolina,charleston,sc, United States, digestive disease center,medical university of south carolina,charleston,sc, United States, department of medicine,duke university medical center,durham,nc,united states,carteret medical group,morehead city,nc, United States, department of internal medicine,st. louis university school of medicine,st louis,mo, United States, department of medicine,indiana university school of medicine,indianapolis,in, United States, dartmouth-hitchcock medical center,hanover,nh, United States, north mississippi medical center,tupelo,ms, United States, department of medicine,division of gastroenterology,hepatology and nutrition,university of pittsburgh,pittsburgh,pa, United States, division of gastroenterology,hepatology and nutrition,virginia commonwealth university medical center,richmond,va,united states,st mary's hospital,richmond,va, United States, department of medicine,division of gastroenterology,hepatology and nutrition,university of pittsburgh,pittsburgh,pa, United States, department of medicine,division of gastroenterology,hepatology and nutrition,university of pittsburgh,pittsburgh,pa, United States, department of medicine,division of gastroenterology,hepatology and nutrition,university of pittsburgh,pittsburgh,pa, United States, department of human genetics,university of pittsburgh,pittsburgh,pa, United States, department of computational and systems biology,university of pittsburgh,pittsburgh,pa, United States, department of pharmacology and brain korea 21 plus project for medical science,yonsei university college of medicine,seoul, South Korea, department of medicine,division of gastroenterology,hepatology and nutrition,university of pittsburgh,pittsburgh,pa,united states,department of human genetics,university of pittsburgh,pittsburgh,pa,united states,department of cell biology and molecular physiology,university of pittsburgh,pittsburgh,pa, United States
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Authors
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