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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mutations of <bold><italic>DNAI1</italic>
</bold>
in Primary Ciliary Dyskinesia</title>
<author><name sortKey="Zariwala, Maimoona A" sort="Zariwala, Maimoona A" uniqKey="Zariwala M" first="Maimoona A." last="Zariwala">Maimoona A. Zariwala</name>
</author>
<author><name sortKey="Leigh, Margaret W" sort="Leigh, Margaret W" uniqKey="Leigh M" first="Margaret W." last="Leigh">Margaret W. Leigh</name>
</author>
<author><name sortKey="Ceppa, Franck" sort="Ceppa, Franck" uniqKey="Ceppa F" first="Franck" last="Ceppa">Franck Ceppa</name>
</author>
<author><name sortKey="Kennedy, Marcus P" sort="Kennedy, Marcus P" uniqKey="Kennedy M" first="Marcus P." last="Kennedy">Marcus P. Kennedy</name>
</author>
<author><name sortKey="Noone, Peadar G" sort="Noone, Peadar G" uniqKey="Noone P" first="Peadar G." last="Noone">Peadar G. Noone</name>
</author>
<author><name sortKey="Carson, Johnny L" sort="Carson, Johnny L" uniqKey="Carson J" first="Johnny L." last="Carson">Johnny L. Carson</name>
</author>
<author><name sortKey="Hazucha, Milan J" sort="Hazucha, Milan J" uniqKey="Hazucha M" first="Milan J." last="Hazucha">Milan J. Hazucha</name>
</author>
<author><name sortKey="Lori, Adriana" sort="Lori, Adriana" uniqKey="Lori A" first="Adriana" last="Lori">Adriana Lori</name>
</author>
<author><name sortKey="Horvath, Judit" sort="Horvath, Judit" uniqKey="Horvath J" first="Judit" last="Horvath">Judit Horvath</name>
</author>
<author><name sortKey="Olbrich, Heike" sort="Olbrich, Heike" uniqKey="Olbrich H" first="Heike" last="Olbrich">Heike Olbrich</name>
</author>
<author><name sortKey="Loges, Niki T" sort="Loges, Niki T" uniqKey="Loges N" first="Niki T." last="Loges">Niki T. Loges</name>
</author>
<author><name sortKey="Bridoux, Anne Marie" sort="Bridoux, Anne Marie" uniqKey="Bridoux A" first="Anne-Marie" last="Bridoux">Anne-Marie Bridoux</name>
</author>
<author><name sortKey="Pennarun, Gaelle" sort="Pennarun, Gaelle" uniqKey="Pennarun G" first="Gaëlle" last="Pennarun">Gaëlle Pennarun</name>
</author>
<author><name sortKey="Duriez, Benedicte" sort="Duriez, Benedicte" uniqKey="Duriez B" first="Bénédicte" last="Duriez">Bénédicte Duriez</name>
</author>
<author><name sortKey="Escudier, Estelle" sort="Escudier, Estelle" uniqKey="Escudier E" first="Estelle" last="Escudier">Estelle Escudier</name>
</author>
<author><name sortKey="Mitchison, Hannah M" sort="Mitchison, Hannah M" uniqKey="Mitchison H" first="Hannah M." last="Mitchison">Hannah M. Mitchison</name>
</author>
<author><name sortKey="Chodhari, Rahul" sort="Chodhari, Rahul" uniqKey="Chodhari R" first="Rahul" last="Chodhari">Rahul Chodhari</name>
</author>
<author><name sortKey="Chung, Eddie M K" sort="Chung, Eddie M K" uniqKey="Chung E" first="Eddie M. K." last="Chung">Eddie M. K. Chung</name>
</author>
<author><name sortKey="Morgan, Lucy C" sort="Morgan, Lucy C" uniqKey="Morgan L" first="Lucy C." last="Morgan">Lucy C. Morgan</name>
</author>
<author><name sortKey="De Iongh, Robbert U" sort="De Iongh, Robbert U" uniqKey="De Iongh R" first="Robbert U." last="De Iongh">Robbert U. De Iongh</name>
</author>
<author><name sortKey="Rutland, Jonathan" sort="Rutland, Jonathan" uniqKey="Rutland J" first="Jonathan" last="Rutland">Jonathan Rutland</name>
</author>
<author><name sortKey="Pradal, Ugo" sort="Pradal, Ugo" uniqKey="Pradal U" first="Ugo" last="Pradal">Ugo Pradal</name>
</author>
<author><name sortKey="Omran, Heymut" sort="Omran, Heymut" uniqKey="Omran H" first="Heymut" last="Omran">Heymut Omran</name>
</author>
<author><name sortKey="Amselem, Serge" sort="Amselem, Serge" uniqKey="Amselem S" first="Serge" last="Amselem">Serge Amselem</name>
</author>
<author><name sortKey="Knowles, Michael R" sort="Knowles, Michael R" uniqKey="Knowles M" first="Michael R." last="Knowles">Michael R. Knowles</name>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">16858015</idno>
<idno type="pmc">2648054</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2648054</idno>
<idno type="RBID">PMC:2648054</idno>
<idno type="doi">10.1164/rccm.200603-370OC</idno>
<date when="2006">2006</date>
<idno type="wicri:Area/Pmc/Corpus">000F36</idno>
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</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutations of <bold><italic>DNAI1</italic>
</bold>
in Primary Ciliary Dyskinesia</title>
<author><name sortKey="Zariwala, Maimoona A" sort="Zariwala, Maimoona A" uniqKey="Zariwala M" first="Maimoona A." last="Zariwala">Maimoona A. Zariwala</name>
</author>
<author><name sortKey="Leigh, Margaret W" sort="Leigh, Margaret W" uniqKey="Leigh M" first="Margaret W." last="Leigh">Margaret W. Leigh</name>
</author>
<author><name sortKey="Ceppa, Franck" sort="Ceppa, Franck" uniqKey="Ceppa F" first="Franck" last="Ceppa">Franck Ceppa</name>
</author>
<author><name sortKey="Kennedy, Marcus P" sort="Kennedy, Marcus P" uniqKey="Kennedy M" first="Marcus P." last="Kennedy">Marcus P. Kennedy</name>
</author>
<author><name sortKey="Noone, Peadar G" sort="Noone, Peadar G" uniqKey="Noone P" first="Peadar G." last="Noone">Peadar G. Noone</name>
</author>
<author><name sortKey="Carson, Johnny L" sort="Carson, Johnny L" uniqKey="Carson J" first="Johnny L." last="Carson">Johnny L. Carson</name>
</author>
<author><name sortKey="Hazucha, Milan J" sort="Hazucha, Milan J" uniqKey="Hazucha M" first="Milan J." last="Hazucha">Milan J. Hazucha</name>
</author>
<author><name sortKey="Lori, Adriana" sort="Lori, Adriana" uniqKey="Lori A" first="Adriana" last="Lori">Adriana Lori</name>
</author>
<author><name sortKey="Horvath, Judit" sort="Horvath, Judit" uniqKey="Horvath J" first="Judit" last="Horvath">Judit Horvath</name>
</author>
<author><name sortKey="Olbrich, Heike" sort="Olbrich, Heike" uniqKey="Olbrich H" first="Heike" last="Olbrich">Heike Olbrich</name>
</author>
<author><name sortKey="Loges, Niki T" sort="Loges, Niki T" uniqKey="Loges N" first="Niki T." last="Loges">Niki T. Loges</name>
</author>
<author><name sortKey="Bridoux, Anne Marie" sort="Bridoux, Anne Marie" uniqKey="Bridoux A" first="Anne-Marie" last="Bridoux">Anne-Marie Bridoux</name>
</author>
<author><name sortKey="Pennarun, Gaelle" sort="Pennarun, Gaelle" uniqKey="Pennarun G" first="Gaëlle" last="Pennarun">Gaëlle Pennarun</name>
</author>
<author><name sortKey="Duriez, Benedicte" sort="Duriez, Benedicte" uniqKey="Duriez B" first="Bénédicte" last="Duriez">Bénédicte Duriez</name>
</author>
<author><name sortKey="Escudier, Estelle" sort="Escudier, Estelle" uniqKey="Escudier E" first="Estelle" last="Escudier">Estelle Escudier</name>
</author>
<author><name sortKey="Mitchison, Hannah M" sort="Mitchison, Hannah M" uniqKey="Mitchison H" first="Hannah M." last="Mitchison">Hannah M. Mitchison</name>
</author>
<author><name sortKey="Chodhari, Rahul" sort="Chodhari, Rahul" uniqKey="Chodhari R" first="Rahul" last="Chodhari">Rahul Chodhari</name>
</author>
<author><name sortKey="Chung, Eddie M K" sort="Chung, Eddie M K" uniqKey="Chung E" first="Eddie M. K." last="Chung">Eddie M. K. Chung</name>
</author>
<author><name sortKey="Morgan, Lucy C" sort="Morgan, Lucy C" uniqKey="Morgan L" first="Lucy C." last="Morgan">Lucy C. Morgan</name>
</author>
<author><name sortKey="De Iongh, Robbert U" sort="De Iongh, Robbert U" uniqKey="De Iongh R" first="Robbert U." last="De Iongh">Robbert U. De Iongh</name>
</author>
<author><name sortKey="Rutland, Jonathan" sort="Rutland, Jonathan" uniqKey="Rutland J" first="Jonathan" last="Rutland">Jonathan Rutland</name>
</author>
<author><name sortKey="Pradal, Ugo" sort="Pradal, Ugo" uniqKey="Pradal U" first="Ugo" last="Pradal">Ugo Pradal</name>
</author>
<author><name sortKey="Omran, Heymut" sort="Omran, Heymut" uniqKey="Omran H" first="Heymut" last="Omran">Heymut Omran</name>
</author>
<author><name sortKey="Amselem, Serge" sort="Amselem, Serge" uniqKey="Amselem S" first="Serge" last="Amselem">Serge Amselem</name>
</author>
<author><name sortKey="Knowles, Michael R" sort="Knowles, Michael R" uniqKey="Knowles M" first="Michael R." last="Knowles">Michael R. Knowles</name>
</author>
</analytic>
<series><title level="j">American Journal of Respiratory and Critical Care Medicine</title>
<idno type="ISSN">1073-449X</idno>
<idno type="eISSN">1535-4970</idno>
<imprint><date when="2006">2006</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p><italic>Rationale:</italic>
Primary ciliary dyskinesia (PCD) is a rare, usually autosomal recessive, genetic disorder characterized by ciliary dysfunction, sino-pulmonary disease, and situs inversus. Disease-causing mutations have been reported in <italic>DNAI1</italic>
and <italic>DNAH5</italic>
encoding outer dynein arm (ODA) proteins of cilia.</p>
<p><italic>Objectives:</italic>
We analyzed <italic>DNAI1</italic>
to identify disease-causing mutations in PCD and to determine if the previously reported IVS1+2_3insT (219+3insT) mutation represents a “founder” or “hot spot” mutation.</p>
<p><italic>Methods:</italic>
Patients with PCD from 179 unrelated families were studied. Exclusion mapping showed no linkage to <italic>DNAI1</italic>
for 13 families; the entire coding region was sequenced in a patient from the remaining 166 families. Reverse transcriptase–polymerase chain reaction (RT-PCR) was performed on nasal epithelial RNA in 14 families.</p>
<p><italic>Results:</italic>
Mutations in <italic>DNAI1</italic>
including 12 novel mutations were identified in 16 of 179 (9%) families; 14 harbored biallelic mutations. Deep intronic splice mutations were not identified by reverse transcriptase–polymerase chain reaction. The prevalence of mutations in families with defined ODA defect was 13%; no mutations were found in patients without a defined ODA defect. The previously reported IVS1+2_3insT mutation accounted for 57% (17/30) of mutant alleles, and marker analysis indicates a common founder for this mutation. Seven mutations occurred in three exons (13, 16, and 17); taken together with previous reports, these three exons are emerging as mutation clusters harboring 29% (12/42) of mutant alleles.</p>
<p><italic>Conclusions:</italic>
A total of 10% of patients with PCD are estimated to harbor mutations in <italic>DNAI1</italic>
; most occur as a common founder IVS1+2_3insT or in exons 13, 16, and 17. This information is useful for establishing a clinical molecular genetic test for PCD.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Respir Crit Care Med</journal-id>
<journal-id journal-id-type="publisher-id">ajrccm</journal-id>
<journal-title>American Journal of Respiratory and Critical Care Medicine</journal-title>
<issn pub-type="ppub">1073-449X</issn>
<issn pub-type="epub">1535-4970</issn>
<publisher><publisher-name>American Thoracic Society</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">16858015</article-id>
<article-id pub-id-type="pmc">2648054</article-id>
<article-id pub-id-type="publisher-id">ajrccm1748858</article-id>
<article-id pub-id-type="doi">10.1164/rccm.200603-370OC</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>A. Airway Biology</subject>
</subj-group>
</article-categories>
<title-group><article-title>Mutations of <bold><italic>DNAI1</italic>
</bold>
in Primary Ciliary Dyskinesia</article-title>
<subtitle>Evidence of Founder Effect in a Common Mutation</subtitle>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Zariwala</surname>
<given-names>Maimoona A.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Leigh</surname>
<given-names>Margaret W.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Ceppa</surname>
<given-names>Franck</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Kennedy</surname>
<given-names>Marcus P.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Noone</surname>
<given-names>Peadar G.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Carson</surname>
<given-names>Johnny L.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Hazucha</surname>
<given-names>Milan J.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Lori</surname>
<given-names>Adriana</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Horvath</surname>
<given-names>Judit</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Olbrich</surname>
<given-names>Heike</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Loges</surname>
<given-names>Niki T.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Bridoux</surname>
<given-names>Anne-Marie</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Pennarun</surname>
<given-names>Gaëlle</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Duriez</surname>
<given-names>Bénédicte</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Escudier</surname>
<given-names>Estelle</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Mitchison</surname>
<given-names>Hannah M.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Chodhari</surname>
<given-names>Rahul</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Chung</surname>
<given-names>Eddie M. K.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Morgan</surname>
<given-names>Lucy C.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>de Iongh</surname>
<given-names>Robbert U.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Rutland</surname>
<given-names>Jonathan</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Pradal</surname>
<given-names>Ugo</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Omran</surname>
<given-names>Heymut</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Amselem</surname>
<given-names>Serge</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Knowles</surname>
<given-names>Michael R.</given-names>
</name>
</contrib>
</contrib-group>
<aff id="N0x1cdd3d0N0x3af76e0">University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Institut de la Santé et de la Recherche Médicale, Créteil, France; Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany; Royal Free and University College Medical School, London, United Kingdom; Concord Hospital, Sydney; Anatomy & Cell Biology, University of Melbourne, Melbourne, Australia; and Cystic Fibrosis Center, Verona, Italy</aff>
<author-notes><fn><p>Correspondence and requests for reprints should be addressed to Maimoona Zariwala, Ph.D., F.A.C.M.G., The University of North Carolina at Chapel Hill, Department of Pathology and Laboratory Medicine, CB# 7248, 7123 Thurston-Bowles Bldg., Chapel Hill, NC 27599-7248. E-mail: <email>zariwala@med.unc.edu</email>
</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>15</day>
<month>10</month>
<year>2006</year>
</pub-date>
<pub-date pub-type="epub"><day>20</day>
<month>7</month>
<year>2006</year>
</pub-date>
<volume>174</volume>
<issue>8</issue>
<fpage>858</fpage>
<lpage>866</lpage>
<history><date date-type="received"><day>13</day>
<month>3</month>
<year>2006</year>
</date>
<date date-type="accepted"><day>17</day>
<month>7</month>
<year>2006</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2006, American Thoracic Society</copyright-statement>
</permissions>
<self-uri xlink:title="pdf" xlink:href="AJRCCM1748858.pdf"></self-uri>
<abstract><p><italic>Rationale:</italic>
Primary ciliary dyskinesia (PCD) is a rare, usually autosomal recessive, genetic disorder characterized by ciliary dysfunction, sino-pulmonary disease, and situs inversus. Disease-causing mutations have been reported in <italic>DNAI1</italic>
and <italic>DNAH5</italic>
encoding outer dynein arm (ODA) proteins of cilia.</p>
<p><italic>Objectives:</italic>
We analyzed <italic>DNAI1</italic>
to identify disease-causing mutations in PCD and to determine if the previously reported IVS1+2_3insT (219+3insT) mutation represents a “founder” or “hot spot” mutation.</p>
<p><italic>Methods:</italic>
Patients with PCD from 179 unrelated families were studied. Exclusion mapping showed no linkage to <italic>DNAI1</italic>
for 13 families; the entire coding region was sequenced in a patient from the remaining 166 families. Reverse transcriptase–polymerase chain reaction (RT-PCR) was performed on nasal epithelial RNA in 14 families.</p>
<p><italic>Results:</italic>
Mutations in <italic>DNAI1</italic>
including 12 novel mutations were identified in 16 of 179 (9%) families; 14 harbored biallelic mutations. Deep intronic splice mutations were not identified by reverse transcriptase–polymerase chain reaction. The prevalence of mutations in families with defined ODA defect was 13%; no mutations were found in patients without a defined ODA defect. The previously reported IVS1+2_3insT mutation accounted for 57% (17/30) of mutant alleles, and marker analysis indicates a common founder for this mutation. Seven mutations occurred in three exons (13, 16, and 17); taken together with previous reports, these three exons are emerging as mutation clusters harboring 29% (12/42) of mutant alleles.</p>
<p><italic>Conclusions:</italic>
A total of 10% of patients with PCD are estimated to harbor mutations in <italic>DNAI1</italic>
; most occur as a common founder IVS1+2_3insT or in exons 13, 16, and 17. This information is useful for establishing a clinical molecular genetic test for PCD.</p>
</abstract>
<kwd-group><kwd>cilia</kwd>
<kwd>dynein</kwd>
<kwd>dextrocardia</kwd>
<kwd>Kartagener syndrome</kwd>
<kwd>mutation</kwd>
</kwd-group>
</article-meta>
<notes><fn-group><fn><p>Supported by grants GCRC 00046, MO1 RR00046-42, 1 RO1 HL071798, Deutsch Forschungsgemeinschaft (SFB592 and DFG Om6/2), GIS Maladies Rares A03091, the ANR Maladies Rares, the Assistance Publique-Hôpitaux de Paris (CRC 96125), Concord Hospital, the Medical Research Council (UK), the Milena Carvajal Pro-Kartagener Foundation, the Wellcome Trust (UK), and grant 5 U54 RR019480 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.</p>
</fn>
<fn><p>This article has an online supplement, which is accessible from this issue's table of contents at <ext-link ext-link-type="uri" xlink:href="www.atsjournals.org">www.atsjournals.org</ext-link>
</p>
</fn>
<fn><p>Originally Published in Press as DOI: 10.1164/rccm.200603-370OC on August 3, 2006</p>
</fn>
<fn><p><bold><italic>Conflict of Interest Statement</italic>
:</bold>
M.A.Z. is a coinvestigator on a research grant from the North Carolina Technology Center to develop assays relating to DNAI1. The grant amount is $250,000 for the total of 2 yr (June 1, 2006 through May 31, 2008). No work in the current study was supported by this grant. M.W.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.P.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.G.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.L.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.J.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.T.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.-M.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.M.K.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.U.d.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. U.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.R.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.</p>
</fn>
</fn-group>
</notes>
</front>
</pmc>
</record>
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