Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis
Identifieur interne : 000D21 ( Pmc/Checkpoint ); précédent : 000D20; suivant : 000D22Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis
Auteurs : Jessica Larusch [États-Unis] ; Jinsei Jung [Corée du Sud] ; Ignacio J. General [États-Unis] ; Michele D. Lewis [États-Unis] ; Hyun Woo Park [Corée du Sud] ; Randall E. Brand [États-Unis] ; Andres Gelrud [États-Unis] ; Michelle A. Anderson [États-Unis] ; Peter A. Banks [États-Unis] ; Darwin Conwell [États-Unis] ; Christopher Lawrence [États-Unis] ; Joseph Romagnuolo [États-Unis] ; John Baillie [États-Unis] ; Samer Alkaade [États-Unis] ; Gregory Cote [États-Unis] ; Timothy B. Gardner [États-Unis] ; Stephen T. Amann [États-Unis] ; Adam Slivka [États-Unis] ; Bimaljit Sandhu [États-Unis] ; Amy Aloe [États-Unis] ; Michelle L. Kienholz [États-Unis] ; Dhiraj Yadav [États-Unis] ; M. Michael Barmada [États-Unis] ; Ivet Bahar [États-Unis] ; Min Goo Lee [Corée du Sud] ; David C. Whitcomb [États-Unis]Source :
- PLoS Genetics [ 1553-7390 ] ; 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 (
Url:
DOI: 10.1371/journal.pgen.1004376
PubMed: 25033378
PubMed Central: 4102440
Affiliations:
- Corée du Sud, États-Unis
- Caroline du Nord, Caroline du Sud, Floride, Indiana, Massachusetts, Michigan, Missouri (État), New Hampshire, Pennsylvanie, Région capitale de Séoul, Virginie, État du Mississippi
- Pittsburgh, Séoul
- Université de Pittsburgh
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PMC:4102440Le document en format XML
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Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis</title>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mechanisms of <italic>CFTR</italic>
Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis</title>
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<author><name sortKey="Jung, Jinsei" sort="Jung, Jinsei" uniqKey="Jung J" first="Jinsei" last="Jung">Jinsei Jung</name>
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</nlm:aff>
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<affiliation wicri:level="3"><nlm:aff id="aff2"><addr-line>Department of Pharmacology and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea</addr-line>
</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Brand, Randall E" sort="Brand, Randall E" uniqKey="Brand R" first="Randall E." last="Brand">Randall E. Brand</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
</author>
<author><name sortKey="Gelrud, Andres" sort="Gelrud, Andres" uniqKey="Gelrud A" first="Andres" last="Gelrud">Andres Gelrud</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
</author>
<author><name sortKey="Anderson, Michelle A" sort="Anderson, Michelle A" uniqKey="Anderson M" first="Michelle A." last="Anderson">Michelle A. Anderson</name>
<affiliation wicri:level="2"><nlm:aff id="aff5"><addr-line>Department of Medicine, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, University of Michigan, Ann Arbor, Michigan</wicri:regionArea>
<placeName><region type="state">Michigan</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Banks, Peter A" sort="Banks, Peter A" uniqKey="Banks P" first="Peter A." last="Banks">Peter A. Banks</name>
<affiliation wicri:level="2"><nlm:aff id="aff6"><addr-line>Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Conwell, Darwin" sort="Conwell, Darwin" uniqKey="Conwell D" first="Darwin" last="Conwell">Darwin Conwell</name>
<affiliation wicri:level="2"><nlm:aff id="aff6"><addr-line>Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lawrence, Christopher" sort="Lawrence, Christopher" uniqKey="Lawrence C" first="Christopher" last="Lawrence">Christopher Lawrence</name>
<affiliation wicri:level="2"><nlm:aff id="aff7"><addr-line>Digestive Disease Center, Medical University of South Carolina, Charleston, South Carolina, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Digestive Disease Center, Medical University of South Carolina, Charleston, South Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Sud</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Romagnuolo, Joseph" sort="Romagnuolo, Joseph" uniqKey="Romagnuolo J" first="Joseph" last="Romagnuolo">Joseph Romagnuolo</name>
<affiliation wicri:level="2"><nlm:aff id="aff7"><addr-line>Digestive Disease Center, Medical University of South Carolina, Charleston, South Carolina, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Digestive Disease Center, Medical University of South Carolina, Charleston, South Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Sud</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Baillie, John" sort="Baillie, John" uniqKey="Baillie J" first="John" last="Baillie">John Baillie</name>
<affiliation wicri:level="2"><nlm:aff id="aff8"><addr-line>Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Duke University Medical Center, Durham, North Carolina</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Alkaade, Samer" sort="Alkaade, Samer" uniqKey="Alkaade S" first="Samer" last="Alkaade">Samer Alkaade</name>
<affiliation wicri:level="2"><nlm:aff id="aff9"><addr-line>Department of Internal Medicine, St. Louis University School of Medicine, St Louis, Missouri, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Internal Medicine, St. Louis University School of Medicine, St Louis, Missouri</wicri:regionArea>
<placeName><region type="state">Missouri (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cote, Gregory" sort="Cote, Gregory" uniqKey="Cote G" first="Gregory" last="Cote">Gregory Cote</name>
<affiliation wicri:level="2"><nlm:aff id="aff10"><addr-line>Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana</wicri:regionArea>
<placeName><region type="state">Indiana</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gardner, Timothy B" sort="Gardner, Timothy B" uniqKey="Gardner T" first="Timothy B." last="Gardner">Timothy B. Gardner</name>
<affiliation wicri:level="2"><nlm:aff id="aff11"><addr-line>Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire</wicri:regionArea>
<placeName><region type="state">New Hampshire</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Amann, Stephen T" sort="Amann, Stephen T" uniqKey="Amann S" first="Stephen T." last="Amann">Stephen T. Amann</name>
<affiliation wicri:level="2"><nlm:aff id="aff12"><addr-line>North Mississippi Medical Center, Tupelo, Mississippi, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>North Mississippi Medical Center, Tupelo, Mississippi</wicri:regionArea>
<placeName><region type="state">État du Mississippi</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Slivka, Adam" sort="Slivka, Adam" uniqKey="Slivka A" first="Adam" last="Slivka">Adam Slivka</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
</author>
<author><name sortKey="Sandhu, Bimaljit" sort="Sandhu, Bimaljit" uniqKey="Sandhu B" first="Bimaljit" last="Sandhu">Bimaljit Sandhu</name>
<affiliation wicri:level="2"><nlm:aff id="aff13"><addr-line>Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center, Richmond, Virginia, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center, Richmond, Virginia</wicri:regionArea>
<placeName><region type="state">Virginie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Aloe, Amy" sort="Aloe, Amy" uniqKey="Aloe A" first="Amy" last="Aloe">Amy Aloe</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
</author>
<author><name sortKey="Kienholz, Michelle L" sort="Kienholz, Michelle L" uniqKey="Kienholz M" first="Michelle L." last="Kienholz">Michelle L. Kienholz</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
</author>
<author><name sortKey="Yadav, Dhiraj" sort="Yadav, Dhiraj" uniqKey="Yadav D" first="Dhiraj" last="Yadav">Dhiraj Yadav</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
</author>
<author><name sortKey="Barmada, M Michael" sort="Barmada, M Michael" uniqKey="Barmada M" first="M. Michael" last="Barmada">M. Michael Barmada</name>
<affiliation wicri:level="4"><nlm:aff id="aff14"><addr-line>Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
</author>
<author><name sortKey="Bahar, Ivet" sort="Bahar, Ivet" uniqKey="Bahar I" first="Ivet" last="Bahar">Ivet Bahar</name>
<affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
</author>
<author><name sortKey="Lee, Min Goo" sort="Lee, Min Goo" uniqKey="Lee M" first="Min Goo" last="Lee">Min Goo Lee</name>
<affiliation wicri:level="3"><nlm:aff id="aff2"><addr-line>Department of Pharmacology and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea</addr-line>
</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Whitcomb, David C" sort="Whitcomb, David C" uniqKey="Whitcomb D" first="David C." last="Whitcomb">David C. Whitcomb</name>
<affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff14"><addr-line>Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="aff15"><addr-line>Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
</author>
</analytic>
<series><title level="j">PLoS Genetics</title>
<idno type="ISSN">1553-7390</idno>
<idno type="eISSN">1553-7404</idno>
<imprint><date when="2014">2014</date>
</imprint>
</series>
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<profileDesc><textClass></textClass>
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<front><div type="abstract" xml:lang="en"><p>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 (<italic>CFTR<sup>sev</sup>
</italic>
) 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 <italic>CFTR</italic>
mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (<italic>CFTR<sup>BD</sup>
</italic>
) 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 <italic>CFTR<sup>BD</sup>
</italic>
mutations from among 81 previously described <italic>CFTR</italic>
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 <italic>CFTR<sup>BD</sup>
</italic>
variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (<italic>CFTR</italic>
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, <italic>CFTR<sup>BD</sup>
</italic>
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 <italic>CFTR<sup>BD</sup>
</italic>
variants through multiple mechanisms. <italic>CFTR<sup>BD</sup>
</italic>
variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.</p>
</div>
</front>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Genet</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Genet</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosgen</journal-id>
<journal-title-group><journal-title>PLoS Genetics</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-7390</issn>
<issn pub-type="epub">1553-7404</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25033378</article-id>
<article-id pub-id-type="pmc">4102440</article-id>
<article-id pub-id-type="publisher-id">PGENETICS-D-13-02984</article-id>
<article-id pub-id-type="doi">10.1371/journal.pgen.1004376</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Anatomy</subject>
<subj-group><subject>Endocrine System</subject>
<subj-group><subject>Pancreas</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Proteins</subject>
</subj-group>
</subj-group>
<subj-group><subject>Developmental Biology</subject>
<subj-group><subject>Fibrosis</subject>
<subj-group><subject>Cystic Fibrosis</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Genetics</subject>
<subj-group><subject>Genetic Dominance</subject>
<subj-group><subject>Autosomal Recessive Traits</subject>
</subj-group>
</subj-group>
<subj-group><subject>Human Genetics</subject>
</subj-group>
</subj-group>
<subj-group><subject>Physiology</subject>
<subj-group><subject>Electrophysiology</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Clinical Genetics</subject>
</subj-group>
<subj-group><subject>Gastroenterology and Hepatology</subject>
</subj-group>
<subj-group><subject>Pulmonology</subject>
<subj-group><subject>Respiratory Infections</subject>
<subj-group><subject>Upper Respiratory Tract Infections</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Urology</subject>
<subj-group><subject>Infertility</subject>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Mechanisms of <italic>CFTR</italic>
Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis</article-title>
<alt-title alt-title-type="running-head"><italic>CFTR</italic>
Bicarbonate Permeation Variants</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>LaRusch</surname>
<given-names>Jessica</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Jung</surname>
<given-names>Jinsei</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>General</surname>
<given-names>Ignacio J.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lewis</surname>
<given-names>Michele D.</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Park</surname>
<given-names>Hyun Woo</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn1"><sup>¤a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brand</surname>
<given-names>Randall E.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gelrud</surname>
<given-names>Andres</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn2"><sup>¤b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Anderson</surname>
<given-names>Michelle A.</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Banks</surname>
<given-names>Peter A.</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Conwell</surname>
<given-names>Darwin</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
<xref ref-type="author-notes" rid="fn3"><sup>¤c</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lawrence</surname>
<given-names>Christopher</given-names>
</name>
<xref ref-type="aff" rid="aff7"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Romagnuolo</surname>
<given-names>Joseph</given-names>
</name>
<xref ref-type="aff" rid="aff7"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Baillie</surname>
<given-names>John</given-names>
</name>
<xref ref-type="aff" rid="aff8"><sup>8</sup>
</xref>
<xref ref-type="author-notes" rid="fn4"><sup>¤d</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alkaade</surname>
<given-names>Samer</given-names>
</name>
<xref ref-type="aff" rid="aff9"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cote</surname>
<given-names>Gregory</given-names>
</name>
<xref ref-type="aff" rid="aff10"><sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gardner</surname>
<given-names>Timothy B.</given-names>
</name>
<xref ref-type="aff" rid="aff11"><sup>11</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Amann</surname>
<given-names>Stephen T.</given-names>
</name>
<xref ref-type="aff" rid="aff12"><sup>12</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Slivka</surname>
<given-names>Adam</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sandhu</surname>
<given-names>Bimaljit</given-names>
</name>
<xref ref-type="aff" rid="aff13"><sup>13</sup>
</xref>
<xref ref-type="author-notes" rid="fn5"><sup>¤e</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Aloe</surname>
<given-names>Amy</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kienholz</surname>
<given-names>Michelle L.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yadav</surname>
<given-names>Dhiraj</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Barmada</surname>
<given-names>M. Michael</given-names>
</name>
<xref ref-type="aff" rid="aff14"><sup>14</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bahar</surname>
<given-names>Ivet</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
<xref ref-type="author-notes" rid="fn6"><sup>¶</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Min Goo</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn6"><sup>¶</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Whitcomb</surname>
<given-names>David C.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff14"><sup>14</sup>
</xref>
<xref ref-type="aff" rid="aff15"><sup>15</sup>
</xref>
<xref ref-type="author-notes" rid="fn6"><sup>¶</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>the North American Pancreatitis Study Group</collab>
<xref ref-type="author-notes" rid="fn7"><sup>‡</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Department of Pharmacology and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</aff>
<aff id="aff4"><label>4</label>
<addr-line>Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, United States of America</addr-line>
</aff>
<aff id="aff5"><label>5</label>
<addr-line>Department of Medicine, University of Michigan, Ann Arbor, Michigan, United States of America</addr-line>
</aff>
<aff id="aff6"><label>6</label>
<addr-line>Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America</addr-line>
</aff>
<aff id="aff7"><label>7</label>
<addr-line>Digestive Disease Center, Medical University of South Carolina, Charleston, South Carolina, United States of America</addr-line>
</aff>
<aff id="aff8"><label>8</label>
<addr-line>Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America</addr-line>
</aff>
<aff id="aff9"><label>9</label>
<addr-line>Department of Internal Medicine, St. Louis University School of Medicine, St Louis, Missouri, United States of America</addr-line>
</aff>
<aff id="aff10"><label>10</label>
<addr-line>Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America</addr-line>
</aff>
<aff id="aff11"><label>11</label>
<addr-line>Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, United States of America</addr-line>
</aff>
<aff id="aff12"><label>12</label>
<addr-line>North Mississippi Medical Center, Tupelo, Mississippi, United States of America</addr-line>
</aff>
<aff id="aff13"><label>13</label>
<addr-line>Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center, Richmond, Virginia, United States of America</addr-line>
</aff>
<aff id="aff14"><label>14</label>
<addr-line>Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</aff>
<aff id="aff15"><label>15</label>
<addr-line>Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>McCarty</surname>
<given-names>Nael</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>Emory University School of Medicine, United States of Americs</addr-line>
</aff>
<author-notes><corresp id="cor1">* E-mail: <email>whitcomb@pitt.edu</email>
</corresp>
<fn fn-type="conflict"><p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con"><p>Conceived and designed the experiments: IB MMB IJG JL MGL DCW. Performed the experiments: JL JJ IJG HWP AA. Analyzed the data: IB IJG MMB JL MGL DY DCW. Contributed reagents/materials/analysis tools: MDL REB AG MAA PAB DC CL JR JB SA GC TBG STA AS BS. Wrote the paper: IB IJG MLK JL MGL DCW. Ascertained and phenotyped patients: MDL REB AG MAA PAB DC CL JR JB SA TBG STA AS BS.</p>
</fn>
<fn id="fn1" fn-type="current-aff"><label>¤a</label>
<p>Current address: Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California, United States of America</p>
</fn>
<fn id="fn2" fn-type="current-aff"><label>¤b</label>
<p>Current address: University of Chicago, Chicago, Illinois, United States of America</p>
</fn>
<fn id="fn3" fn-type="current-aff"><label>¤c</label>
<p>Current address: The Ohio State University, Columbus, Ohio, United States of America</p>
</fn>
<fn id="fn4" fn-type="current-aff"><label>¤d</label>
<p>Current address: Carteret Medical Group, Morehead City, North Carolina, United States of America</p>
</fn>
<fn id="fn5" fn-type="current-aff"><label>¤e</label>
<p>Current address: St Mary's Hospital, Richmond, Virginia, United States of America</p>
</fn>
<fn id="fn6" fn-type="other"><p>¶ IB, MGL and DCW co-directed this project.</p>
</fn>
<fn id="fn7" fn-type="other"><p>‡ Full membership of the North American Pancreatitis Study Group is provided in the Acknowledgments.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><month>7</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>17</day>
<month>7</month>
<year>2014</year>
</pub-date>
<volume>10</volume>
<issue>7</issue>
<elocation-id>e1004376</elocation-id>
<history><date date-type="received"><day>26</day>
<month>10</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>10</day>
<month>3</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© 2014 Whitcomb et al</copyright-statement>
<copyright-year>2014</copyright-year>
<copyright-holder>Whitcomb et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p>
</license>
</permissions>
<abstract><p>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 (<italic>CFTR<sup>sev</sup>
</italic>
) 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 <italic>CFTR</italic>
mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (<italic>CFTR<sup>BD</sup>
</italic>
) 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 <italic>CFTR<sup>BD</sup>
</italic>
mutations from among 81 previously described <italic>CFTR</italic>
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 <italic>CFTR<sup>BD</sup>
</italic>
variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (<italic>CFTR</italic>
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, <italic>CFTR<sup>BD</sup>
</italic>
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 <italic>CFTR<sup>BD</sup>
</italic>
variants through multiple mechanisms. <italic>CFTR<sup>BD</sup>
</italic>
variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>Genetic disorders of ion channels can affect the body's ability to function properly in many ways. CFTR, an ion channel regulating movement of chloride and bicarbonate across cell membranes, is important for absorbing and secreting fluids. If the gene responsible for the CFTR channel is mutated severely, the result is cystic fibrosis, a hereditary disorder in which the patient develops thick mucus, especially in the lungs, as well as scarring (fibrosis) in the pancreas. Cystic fibrosis also affects the sweat glands, nasal sinuses, intestines, liver, and male reproductive system. Mutations to the CFTR gene that do not cause cystic fibrosis have been considered benign. However, we discovered 9 CFTR mutations that do not cause cystic fibrosis but do cause inflammation and scarring of the pancreas (chronic pancreatitis). These mutant CFTR channels secrete chloride, which is important in the sweat glands, lungs, and intestines, but not bicarbonate, which is important in the pancreas, sinuses, and male reproductive tract. We found patients with any of these 9 mutations had chronic pancreatitis, and often sinus infections, and male infertility, but not other symptoms of cystic fibrosis. Our computer models and data will help researchers develop better drugs and help physicians treating patients with chronic pancreatitis.</p>
</abstract>
<funding-group><funding-statement>The study was supported by R01DK061451 (DCW), R01GM086238 (IB), T32DK063922 (DCW), P30CA047904 (UPCI) and UL1 RR024153 and UL1TR000005 (GPCL, IB, IJG); the paper's contents are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. Funding was also provided by grant A111218-11-PG03 from the National Project for Personalized Genomic Medicine, Ministry for Health & Welfare, Republic of Korea (MGL) and BK 21 Project for Medical Sciences, (JJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><page-count count="15"></page-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Corée du Sud</li>
<li>États-Unis</li>
</country>
<region><li>Caroline du Nord</li>
<li>Caroline du Sud</li>
<li>Floride</li>
<li>Indiana</li>
<li>Massachusetts</li>
<li>Michigan</li>
<li>Missouri (État)</li>
<li>New Hampshire</li>
<li>Pennsylvanie</li>
<li>Région capitale de Séoul</li>
<li>Virginie</li>
<li>État du Mississippi</li>
</region>
<settlement><li>Pittsburgh</li>
<li>Séoul</li>
</settlement>
<orgName><li>Université de Pittsburgh</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Larusch, Jessica" sort="Larusch, Jessica" uniqKey="Larusch J" first="Jessica" last="Larusch">Jessica Larusch</name>
</region>
<name sortKey="Alkaade, Samer" sort="Alkaade, Samer" uniqKey="Alkaade S" first="Samer" last="Alkaade">Samer Alkaade</name>
<name sortKey="Aloe, Amy" sort="Aloe, Amy" uniqKey="Aloe A" first="Amy" last="Aloe">Amy Aloe</name>
<name sortKey="Amann, Stephen T" sort="Amann, Stephen T" uniqKey="Amann S" first="Stephen T." last="Amann">Stephen T. Amann</name>
<name sortKey="Anderson, Michelle A" sort="Anderson, Michelle A" uniqKey="Anderson M" first="Michelle A." last="Anderson">Michelle A. Anderson</name>
<name sortKey="Bahar, Ivet" sort="Bahar, Ivet" uniqKey="Bahar I" first="Ivet" last="Bahar">Ivet Bahar</name>
<name sortKey="Baillie, John" sort="Baillie, John" uniqKey="Baillie J" first="John" last="Baillie">John Baillie</name>
<name sortKey="Banks, Peter A" sort="Banks, Peter A" uniqKey="Banks P" first="Peter A." last="Banks">Peter A. Banks</name>
<name sortKey="Barmada, M Michael" sort="Barmada, M Michael" uniqKey="Barmada M" first="M. Michael" last="Barmada">M. Michael Barmada</name>
<name sortKey="Brand, Randall E" sort="Brand, Randall E" uniqKey="Brand R" first="Randall E." last="Brand">Randall E. Brand</name>
<name sortKey="Conwell, Darwin" sort="Conwell, Darwin" uniqKey="Conwell D" first="Darwin" last="Conwell">Darwin Conwell</name>
<name sortKey="Cote, Gregory" sort="Cote, Gregory" uniqKey="Cote G" first="Gregory" last="Cote">Gregory Cote</name>
<name sortKey="Gardner, Timothy B" sort="Gardner, Timothy B" uniqKey="Gardner T" first="Timothy B." last="Gardner">Timothy B. Gardner</name>
<name sortKey="Gelrud, Andres" sort="Gelrud, Andres" uniqKey="Gelrud A" first="Andres" last="Gelrud">Andres Gelrud</name>
<name sortKey="General, Ignacio J" sort="General, Ignacio J" uniqKey="General I" first="Ignacio J." last="General">Ignacio J. General</name>
<name sortKey="Kienholz, Michelle L" sort="Kienholz, Michelle L" uniqKey="Kienholz M" first="Michelle L." last="Kienholz">Michelle L. Kienholz</name>
<name sortKey="Lawrence, Christopher" sort="Lawrence, Christopher" uniqKey="Lawrence C" first="Christopher" last="Lawrence">Christopher Lawrence</name>
<name sortKey="Lewis, Michele D" sort="Lewis, Michele D" uniqKey="Lewis M" first="Michele D." last="Lewis">Michele D. Lewis</name>
<name sortKey="Romagnuolo, Joseph" sort="Romagnuolo, Joseph" uniqKey="Romagnuolo J" first="Joseph" last="Romagnuolo">Joseph Romagnuolo</name>
<name sortKey="Sandhu, Bimaljit" sort="Sandhu, Bimaljit" uniqKey="Sandhu B" first="Bimaljit" last="Sandhu">Bimaljit Sandhu</name>
<name sortKey="Slivka, Adam" sort="Slivka, Adam" uniqKey="Slivka A" first="Adam" last="Slivka">Adam Slivka</name>
<name sortKey="Whitcomb, David C" sort="Whitcomb, David C" uniqKey="Whitcomb D" first="David C." last="Whitcomb">David C. Whitcomb</name>
<name sortKey="Whitcomb, David C" sort="Whitcomb, David C" uniqKey="Whitcomb D" first="David C." last="Whitcomb">David C. Whitcomb</name>
<name sortKey="Whitcomb, David C" sort="Whitcomb, David C" uniqKey="Whitcomb D" first="David C." last="Whitcomb">David C. Whitcomb</name>
<name sortKey="Yadav, Dhiraj" sort="Yadav, Dhiraj" uniqKey="Yadav D" first="Dhiraj" last="Yadav">Dhiraj Yadav</name>
</country>
<country name="Corée du Sud"><region name="Région capitale de Séoul"><name sortKey="Jung, Jinsei" sort="Jung, Jinsei" uniqKey="Jung J" first="Jinsei" last="Jung">Jinsei Jung</name>
</region>
<name sortKey="Lee, Min Goo" sort="Lee, Min Goo" uniqKey="Lee M" first="Min Goo" last="Lee">Min Goo Lee</name>
<name sortKey="Park, Hyun Woo" sort="Park, Hyun Woo" uniqKey="Park H" first="Hyun Woo" last="Park">Hyun Woo Park</name>
</country>
</tree>
</affiliations>
</record>
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