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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy</title><author><name sortKey="Pelin, Katarina" sort="Pelin, Katarina" uniqKey="Pelin K" first="Katarina" last="Pelin">Katarina Pelin</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Department of Medical Genetics, University of Helsinki, and the Folkhälsan Institute of Genetics, Helsinki, Finland;</nlm:aff></affiliation></author><author><name sortKey="Hilpel, Pirta" sort="Hilpel, Pirta" uniqKey="Hilpel P" first="Pirta" last="Hilpel">Pirta Hilpel</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Department of Medical Genetics, University of Helsinki, and the Folkhälsan Institute of Genetics, Helsinki, Finland;</nlm:aff></affiliation></author><author><name sortKey="Donner, Kati" sort="Donner, Kati" uniqKey="Donner K" first="Kati" last="Donner">Kati Donner</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Department of Medical Genetics, University of Helsinki, and the Folkhälsan Institute of Genetics, Helsinki, Finland;</nlm:aff></affiliation></author><author><name sortKey="Sewry, Caroline" sort="Sewry, Caroline" uniqKey="Sewry C" first="Caroline" last="Sewry">Caroline Sewry</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom;</nlm:aff></affiliation></author><author><name sortKey="Akkari, Patrick A" sort="Akkari, Patrick A" uniqKey="Akkari P" first="Patrick A." last="Akkari">Patrick A. Akkari</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Australian Neuromuscular Research Institute, QEII Medical Centre, University of Western Australia, Nedlands, Australia;</nlm:aff></affiliation></author><author><name sortKey="Wilton, Stephen D" sort="Wilton, Stephen D" uniqKey="Wilton S" first="Stephen D." last="Wilton">Stephen D. Wilton</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Australian Neuromuscular Research Institute, QEII Medical Centre, University of Western Australia, Nedlands, Australia;</nlm:aff></affiliation></author><author><name sortKey="Wattanasirichaigoon, Duangrurdee" sort="Wattanasirichaigoon, Duangrurdee" uniqKey="Wattanasirichaigoon D" first="Duangrurdee" last="Wattanasirichaigoon">Duangrurdee Wattanasirichaigoon</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Genetics Division, Children’s Hospital and Harvard Medical School, Boston, MA 02115;</nlm:aff></affiliation></author><author><name sortKey="Bang, Marie Louise" sort="Bang, Marie Louise" uniqKey="Bang M" first="Marie-Louise" last="Bang">Marie-Louise Bang</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">European Molecular Biology Laboratory, Heidelberg, Germany;</nlm:aff></affiliation></author><author><name sortKey="Centner, Thomas" sort="Centner, Thomas" uniqKey="Centner T" first="Thomas" last="Centner">Thomas Centner</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">European Molecular Biology Laboratory, Heidelberg, Germany;</nlm:aff></affiliation></author><author><name sortKey="Hanefeld, Folker" sort="Hanefeld, Folker" uniqKey="Hanefeld F" first="Folker" last="Hanefeld">Folker Hanefeld</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Georg-August-Universität, Göttingen, Germany;</nlm:aff></affiliation></author><author><name sortKey="Odent, Sylvie" sort="Odent, Sylvie" uniqKey="Odent S" first="Sylvie" last="Odent">Sylvie Odent</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Genetics Department, Rennes University Hospital, Rennes, France;</nlm:aff></affiliation></author><author><name sortKey="Fardeau, Michel" sort="Fardeau, Michel" uniqKey="Fardeau M" first="Michel" last="Fardeau">Michel Fardeau</name><affiliation><nlm:aff wicri:cut="; and" id="N0x8bb7a18.0xa0fa2e8">Institut de Myologie, Hopital de la Salpetriere, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Urtizberea, J Andoni" sort="Urtizberea, J Andoni" uniqKey="Urtizberea J" first="J. Andoni" last="Urtizberea">J. Andoni Urtizberea</name><affiliation><nlm:aff wicri:cut="; and" id="N0x8bb7a18.0xa0fa2e8">Institut de Myologie, Hopital de la Salpetriere, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Muntoni, Francesco" sort="Muntoni, Francesco" uniqKey="Muntoni F" first="Francesco" last="Muntoni">Francesco Muntoni</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom;</nlm:aff></affiliation></author><author><name sortKey="Dubowitz, Victor" sort="Dubowitz, Victor" uniqKey="Dubowitz V" first="Victor" last="Dubowitz">Victor Dubowitz</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom;</nlm:aff></affiliation></author><author><name sortKey="Beggs, Alan H" sort="Beggs, Alan H" uniqKey="Beggs A" first="Alan H." last="Beggs">Alan H. Beggs</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Genetics Division, Children’s Hospital and Harvard Medical School, Boston, MA 02115;</nlm:aff></affiliation></author><author><name sortKey="Laing, Nigel G" sort="Laing, Nigel G" uniqKey="Laing N" first="Nigel G." last="Laing">Nigel G. Laing</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Australian Neuromuscular Research Institute, QEII Medical Centre, University of Western Australia, Nedlands, Australia;</nlm:aff></affiliation></author><author><name sortKey="Labeit, Siegfried" sort="Labeit, Siegfried" uniqKey="Labeit S" first="Siegfried" last="Labeit">Siegfried Labeit</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">European Molecular Biology Laboratory, Heidelberg, Germany;</nlm:aff></affiliation></author><author><name sortKey="De La Chapelle, Albert" sort="De La Chapelle, Albert" uniqKey="De La Chapelle A" first="Albert" last="De La Chapelle">Albert De La Chapelle</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Department of Medical Genetics, University of Helsinki, and the Folkhälsan Institute of Genetics, Helsinki, Finland;</nlm:aff></affiliation><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210</nlm:aff></affiliation></author><author><name sortKey="Wallgren Pettersson, Carina" sort="Wallgren Pettersson, Carina" uniqKey="Wallgren Pettersson C" first="Carina" last="Wallgren-Pettersson">Carina Wallgren-Pettersson</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Department of Medical Genetics, University of Helsinki, and the Folkhälsan Institute of Genetics, Helsinki, Finland;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">10051637</idno><idno type="pmc">26779</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC26779</idno><idno type="RBID">PMC:26779</idno><date when="1999">1999</date><idno type="wicri:Area/Pmc/Corpus">000A22</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A22</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy</title><author><name sortKey="Pelin, Katarina" sort="Pelin, Katarina" uniqKey="Pelin K" first="Katarina" last="Pelin">Katarina Pelin</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Department of Medical Genetics, University of Helsinki, and the Folkhälsan Institute of Genetics, Helsinki, Finland;</nlm:aff></affiliation></author><author><name sortKey="Hilpel, Pirta" sort="Hilpel, Pirta" uniqKey="Hilpel P" first="Pirta" last="Hilpel">Pirta Hilpel</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Department of Medical Genetics, University of Helsinki, and the Folkhälsan Institute of Genetics, Helsinki, Finland;</nlm:aff></affiliation></author><author><name sortKey="Donner, Kati" sort="Donner, Kati" uniqKey="Donner K" first="Kati" last="Donner">Kati Donner</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Department of Medical Genetics, University of Helsinki, and the Folkhälsan Institute of Genetics, Helsinki, Finland;</nlm:aff></affiliation></author><author><name sortKey="Sewry, Caroline" sort="Sewry, Caroline" uniqKey="Sewry C" first="Caroline" last="Sewry">Caroline Sewry</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom;</nlm:aff></affiliation></author><author><name sortKey="Akkari, Patrick A" sort="Akkari, Patrick A" uniqKey="Akkari P" first="Patrick A." last="Akkari">Patrick A. Akkari</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Australian Neuromuscular Research Institute, QEII Medical Centre, University of Western Australia, Nedlands, Australia;</nlm:aff></affiliation></author><author><name sortKey="Wilton, Stephen D" sort="Wilton, Stephen D" uniqKey="Wilton S" first="Stephen D." last="Wilton">Stephen D. Wilton</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Australian Neuromuscular Research Institute, QEII Medical Centre, University of Western Australia, Nedlands, Australia;</nlm:aff></affiliation></author><author><name sortKey="Wattanasirichaigoon, Duangrurdee" sort="Wattanasirichaigoon, Duangrurdee" uniqKey="Wattanasirichaigoon D" first="Duangrurdee" last="Wattanasirichaigoon">Duangrurdee Wattanasirichaigoon</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Genetics Division, Children’s Hospital and Harvard Medical School, Boston, MA 02115;</nlm:aff></affiliation></author><author><name sortKey="Bang, Marie Louise" sort="Bang, Marie Louise" uniqKey="Bang M" first="Marie-Louise" last="Bang">Marie-Louise Bang</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">European Molecular Biology Laboratory, Heidelberg, Germany;</nlm:aff></affiliation></author><author><name sortKey="Centner, Thomas" sort="Centner, Thomas" uniqKey="Centner T" first="Thomas" last="Centner">Thomas Centner</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">European Molecular Biology Laboratory, Heidelberg, Germany;</nlm:aff></affiliation></author><author><name sortKey="Hanefeld, Folker" sort="Hanefeld, Folker" uniqKey="Hanefeld F" first="Folker" last="Hanefeld">Folker Hanefeld</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Georg-August-Universität, Göttingen, Germany;</nlm:aff></affiliation></author><author><name sortKey="Odent, Sylvie" sort="Odent, Sylvie" uniqKey="Odent S" first="Sylvie" last="Odent">Sylvie Odent</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Genetics Department, Rennes University Hospital, Rennes, France;</nlm:aff></affiliation></author><author><name sortKey="Fardeau, Michel" sort="Fardeau, Michel" uniqKey="Fardeau M" first="Michel" last="Fardeau">Michel Fardeau</name><affiliation><nlm:aff wicri:cut="; and" id="N0x8bb7a18.0xa0fa2e8">Institut de Myologie, Hopital de la Salpetriere, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Urtizberea, J Andoni" sort="Urtizberea, J Andoni" uniqKey="Urtizberea J" first="J. Andoni" last="Urtizberea">J. Andoni Urtizberea</name><affiliation><nlm:aff wicri:cut="; and" id="N0x8bb7a18.0xa0fa2e8">Institut de Myologie, Hopital de la Salpetriere, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Muntoni, Francesco" sort="Muntoni, Francesco" uniqKey="Muntoni F" first="Francesco" last="Muntoni">Francesco Muntoni</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom;</nlm:aff></affiliation></author><author><name sortKey="Dubowitz, Victor" sort="Dubowitz, Victor" uniqKey="Dubowitz V" first="Victor" last="Dubowitz">Victor Dubowitz</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom;</nlm:aff></affiliation></author><author><name sortKey="Beggs, Alan H" sort="Beggs, Alan H" uniqKey="Beggs A" first="Alan H." last="Beggs">Alan H. Beggs</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Genetics Division, Children’s Hospital and Harvard Medical School, Boston, MA 02115;</nlm:aff></affiliation></author><author><name sortKey="Laing, Nigel G" sort="Laing, Nigel G" uniqKey="Laing N" first="Nigel G." last="Laing">Nigel G. Laing</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Australian Neuromuscular Research Institute, QEII Medical Centre, University of Western Australia, Nedlands, Australia;</nlm:aff></affiliation></author><author><name sortKey="Labeit, Siegfried" sort="Labeit, Siegfried" uniqKey="Labeit S" first="Siegfried" last="Labeit">Siegfried Labeit</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">European Molecular Biology Laboratory, Heidelberg, Germany;</nlm:aff></affiliation></author><author><name sortKey="De La Chapelle, Albert" sort="De La Chapelle, Albert" uniqKey="De La Chapelle A" first="Albert" last="De La Chapelle">Albert De La Chapelle</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Department of Medical Genetics, University of Helsinki, and the Folkhälsan Institute of Genetics, Helsinki, Finland;</nlm:aff></affiliation><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210</nlm:aff></affiliation></author><author><name sortKey="Wallgren Pettersson, Carina" sort="Wallgren Pettersson, Carina" uniqKey="Wallgren Pettersson C" first="Carina" last="Wallgren-Pettersson">Carina Wallgren-Pettersson</name><affiliation><nlm:aff id="N0x8bb7a18.0xa0fa2e8">Department of Medical Genetics, University of Helsinki, and the Folkhälsan Institute of Genetics, Helsinki, Finland;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="1999">1999</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The congenital nemaline myopathies are rare hereditary muscle disorders characterized by the presence in the muscle fibers of nemaline bodies consisting of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of nemaline myopathy, the disease is caused by a mutation in the α-tropomyosin gene <italic>TPM3</italic>. The typical form of nemaline myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that mutations in the nebulin gene located within this region are associated with the disease. The nebulin protein is a giant protein found in the thin filaments of striated muscle. A variety of nebulin isoforms are thought to contribute to the molecular diversity of Z discs. We have studied the 3′ end of the 20.8-kb cDNA encoding the Z disc part of the 800-kDa protein and describe six disease-associated mutations in patients from five families of different ethnic origins. In two families with consanguineous parents, the patients were homozygous for point mutations. In one family with nonconsanguineous parents, the affected siblings were compound heterozygotes for two different mutations, and in two further families with one detected mutation each, haplotypes are compatible with compound heterozygosity. Immunofluorescence studies with antibodies specific to the C-terminal region of nebulin indicate that the mutations may cause protein truncation possibly associated with loss of fiber-type diversity, which may be relevant to disease pathogenesis.</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">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>The National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">10051637</article-id><article-id pub-id-type="pmc">26779</article-id><article-id pub-id-type="publisher-id">4803</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Medical Sciences</subject></subj-group></subj-group></article-categories><title-group><article-title>Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Pelin</surname><given-names>Katarina</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">*</xref></contrib><contrib contrib-type="author"><name><surname>Hilpelä</surname><given-names>Pirta</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">*</xref></contrib><contrib contrib-type="author"><name><surname>Donner</surname><given-names>Kati</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">*</xref></contrib><contrib contrib-type="author"><name><surname>Sewry</surname><given-names>Caroline</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">†</xref></contrib><contrib contrib-type="author"><name><surname>Akkari</surname><given-names>Patrick A.</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">‡</xref></contrib><contrib contrib-type="author"><name><surname>Wilton</surname><given-names>Stephen D.</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">‡</xref></contrib><contrib contrib-type="author"><name><surname>Wattanasirichaigoon</surname><given-names>Duangrurdee</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">§</xref></contrib><contrib contrib-type="author"><name><surname>Bang</surname><given-names>Marie-Louise</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">¶</xref></contrib><contrib contrib-type="author"><name><surname>Centner</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">¶</xref></contrib><contrib contrib-type="author"><name><surname>Hanefeld</surname><given-names>Folker</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">‖</xref></contrib><contrib contrib-type="author"><name><surname>Odent</surname><given-names>Sylvie</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">**</xref></contrib><contrib contrib-type="author"><name><surname>Fardeau</surname><given-names>Michel</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">‡‡</xref></contrib><contrib contrib-type="author"><name><surname>Urtizberea</surname><given-names>J. Andoni</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">‡‡</xref></contrib><contrib contrib-type="author"><name><surname>Muntoni</surname><given-names>Francesco</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">†</xref></contrib><contrib contrib-type="author"><name><surname>Dubowitz</surname><given-names>Victor</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">†</xref></contrib><contrib contrib-type="author"><name><surname>Beggs</surname><given-names>Alan H.</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">§</xref></contrib><contrib contrib-type="author"><name><surname>Laing</surname><given-names>Nigel G.</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">‡</xref></contrib><contrib contrib-type="author"><name><surname>Labeit</surname><given-names>Siegfried</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">¶</xref></contrib><contrib contrib-type="author"><name><surname>de la Chapelle</surname><given-names>Albert</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">*</xref><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">††</xref></contrib><contrib contrib-type="author"><name><surname>Wallgren-Pettersson</surname><given-names>Carina</given-names></name><xref ref-type="aff" rid="N0x8bb7a18.0xa0fa2e8">*</xref><xref ref-type="author-notes" rid="FN162">§§</xref></contrib></contrib-group><aff id="N0x8bb7a18.0xa0fa2e8"><label>*</label>Department of Medical Genetics, University of Helsinki, and the Folkhälsan Institute of Genetics, Helsinki, Finland;<label>†</label>Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom;<label>‡</label>Australian Neuromuscular Research Institute, QEII Medical Centre, University of Western Australia, Nedlands, Australia;<label>§</label>Genetics Division, Children’s Hospital and Harvard Medical School, Boston, MA 02115;<label>¶</label>European Molecular Biology Laboratory, Heidelberg, Germany;<label>‖</label>Georg-August-Universität, Göttingen, Germany;<label>**</label>Genetics Department, Rennes University Hospital, Rennes, France;<label>‡‡</label>Institut de Myologie, Hopital de la Salpetriere, Paris, France; and<label>††</label>Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210</aff><author-notes><fn id="FN162"><label>§§</label><p>To whom reprint requests should be addressed at: Consultant in Medical Genetics, The Folkhälsan Department of Medical Genetics, P.O. Box 211 (Topeliusgatan 20), FIN-00251 Helsinki, Finland. e-mail: <email>Carina.Wallgren@helsinki.fi</email>.</p></fn><fn><p>Contributed by Albert de la Chapelle</p></fn></author-notes><pub-date pub-type="ppub"><day>2</day><month>3</month><year>1999</year></pub-date><volume>96</volume><issue>5</issue><fpage>2305</fpage><lpage>2310</lpage><history><date date-type="accepted"><day>18</day><month>12</month><year>1998</year></date></history><copyright-statement>Copyright © 1999, The National Academy of Sciences</copyright-statement><copyright-year>1999</copyright-year><abstract><p>The congenital nemaline myopathies are rare hereditary muscle disorders characterized by the presence in the muscle fibers of nemaline bodies consisting of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of nemaline myopathy, the disease is caused by a mutation in the α-tropomyosin gene <italic>TPM3</italic>. The typical form of nemaline myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that mutations in the nebulin gene located within this region are associated with the disease. The nebulin protein is a giant protein found in the thin filaments of striated muscle. A variety of nebulin isoforms are thought to contribute to the molecular diversity of Z discs. We have studied the 3′ end of the 20.8-kb cDNA encoding the Z disc part of the 800-kDa protein and describe six disease-associated mutations in patients from five families of different ethnic origins. In two families with consanguineous parents, the patients were homozygous for point mutations. In one family with nonconsanguineous parents, the affected siblings were compound heterozygotes for two different mutations, and in two further families with one detected mutation each, haplotypes are compatible with compound heterozygosity. Immunofluorescence studies with antibodies specific to the C-terminal region of nebulin indicate that the mutations may cause protein truncation possibly associated with loss of fiber-type diversity, which may be relevant to disease pathogenesis.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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