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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Mutation in the <italic>SOS1</italic> Gene Causes Hereditary Gingival Fibromatosis Type 1</title><author><name sortKey="Hart, Thomas C" sort="Hart, Thomas C" uniqKey="Hart T" first="Thomas C." last="Hart">Thomas C. Hart</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Zhang, Yingze" sort="Zhang, Yingze" uniqKey="Zhang Y" first="Yingze" last="Zhang">Yingze Zhang</name><affiliation><nlm:aff wicri:cut=", and" id="N0x97739c8.0x8be2520">Center For Craniofacial and Dental Genetics, Division of Oral Biology and Pathology, University of Pittsburgh School of Dental Medicine</nlm:aff></affiliation></author><author><name sortKey="Gorry, Michael C" sort="Gorry, Michael C" uniqKey="Gorry M" first="Michael C." last="Gorry">Michael C. Gorry</name><affiliation><nlm:aff wicri:cut=", and" id="N0x97739c8.0x8be2520">Center For Craniofacial and Dental Genetics, Division of Oral Biology and Pathology, University of Pittsburgh School of Dental Medicine</nlm:aff></affiliation></author><author><name sortKey="Hart, P Suzanne" sort="Hart, P Suzanne" uniqKey="Hart P" first="P. Suzanne" last="Hart">P. Suzanne Hart</name><affiliation><nlm:aff wicri:cut="; and" id="N0x97739c8.0x8be2520">Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh</nlm:aff></affiliation></author><author><name sortKey="Cooper, Margaret" sort="Cooper, Margaret" uniqKey="Cooper M" first="Margaret" last="Cooper">Margaret Cooper</name><affiliation><nlm:aff wicri:cut=", and" id="N0x97739c8.0x8be2520">Center For Craniofacial and Dental Genetics, Division of Oral Biology and Pathology, University of Pittsburgh School of Dental Medicine</nlm:aff></affiliation></author><author><name sortKey="Marazita, Mary L" sort="Marazita, Mary L" uniqKey="Marazita M" first="Mary L." last="Marazita">Mary L. Marazita</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Marks, Jared M" sort="Marks, Jared M" uniqKey="Marks J" first="Jared M." last="Marks">Jared M. Marks</name><affiliation><nlm:aff wicri:cut=", and" id="N0x97739c8.0x8be2520">Center For Craniofacial and Dental Genetics, Division of Oral Biology and Pathology, University of Pittsburgh School of Dental Medicine</nlm:aff></affiliation></author><author><name sortKey="Cortelli, Jose R" sort="Cortelli, Jose R" uniqKey="Cortelli J" first="Jose R." last="Cortelli">Jose R. Cortelli</name><affiliation><nlm:aff id="N0x97739c8.0x8be2520">Department of Periodontics, School of Dentistry, University of Taubate, Taubate, Brazil</nlm:aff></affiliation></author><author><name sortKey="Pallos, Debora" sort="Pallos, Debora" uniqKey="Pallos D" first="Debora" last="Pallos">Debora Pallos</name><affiliation><nlm:aff id="N0x97739c8.0x8be2520">Department of Periodontics, School of Dentistry, University of Taubate, Taubate, Brazil</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">11868160</idno><idno type="pmc">379122</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC379122</idno><idno type="RBID">PMC:379122</idno><date when="2002">2002</date><idno type="wicri:Area/Pmc/Corpus">000017</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000017</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Mutation in the <italic>SOS1</italic> Gene Causes Hereditary Gingival Fibromatosis Type 1</title><author><name sortKey="Hart, Thomas C" sort="Hart, Thomas C" uniqKey="Hart T" first="Thomas C." last="Hart">Thomas C. Hart</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Zhang, Yingze" sort="Zhang, Yingze" uniqKey="Zhang Y" first="Yingze" last="Zhang">Yingze Zhang</name><affiliation><nlm:aff wicri:cut=", and" id="N0x97739c8.0x8be2520">Center For Craniofacial and Dental Genetics, Division of Oral Biology and Pathology, University of Pittsburgh School of Dental Medicine</nlm:aff></affiliation></author><author><name sortKey="Gorry, Michael C" sort="Gorry, Michael C" uniqKey="Gorry M" first="Michael C." last="Gorry">Michael C. Gorry</name><affiliation><nlm:aff wicri:cut=", and" id="N0x97739c8.0x8be2520">Center For Craniofacial and Dental Genetics, Division of Oral Biology and Pathology, University of Pittsburgh School of Dental Medicine</nlm:aff></affiliation></author><author><name sortKey="Hart, P Suzanne" sort="Hart, P Suzanne" uniqKey="Hart P" first="P. Suzanne" last="Hart">P. Suzanne Hart</name><affiliation><nlm:aff wicri:cut="; and" id="N0x97739c8.0x8be2520">Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh</nlm:aff></affiliation></author><author><name sortKey="Cooper, Margaret" sort="Cooper, Margaret" uniqKey="Cooper M" first="Margaret" last="Cooper">Margaret Cooper</name><affiliation><nlm:aff wicri:cut=", and" id="N0x97739c8.0x8be2520">Center For Craniofacial and Dental Genetics, Division of Oral Biology and Pathology, University of Pittsburgh School of Dental Medicine</nlm:aff></affiliation></author><author><name sortKey="Marazita, Mary L" sort="Marazita, Mary L" uniqKey="Marazita M" first="Mary L." last="Marazita">Mary L. Marazita</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Marks, Jared M" sort="Marks, Jared M" uniqKey="Marks J" first="Jared M." last="Marks">Jared M. Marks</name><affiliation><nlm:aff wicri:cut=", and" id="N0x97739c8.0x8be2520">Center For Craniofacial and Dental Genetics, Division of Oral Biology and Pathology, University of Pittsburgh School of Dental Medicine</nlm:aff></affiliation></author><author><name sortKey="Cortelli, Jose R" sort="Cortelli, Jose R" uniqKey="Cortelli J" first="Jose R." last="Cortelli">Jose R. Cortelli</name><affiliation><nlm:aff id="N0x97739c8.0x8be2520">Department of Periodontics, School of Dentistry, University of Taubate, Taubate, Brazil</nlm:aff></affiliation></author><author><name sortKey="Pallos, Debora" sort="Pallos, Debora" uniqKey="Pallos D" first="Debora" last="Pallos">Debora Pallos</name><affiliation><nlm:aff id="N0x97739c8.0x8be2520">Department of Periodontics, School of Dentistry, University of Taubate, Taubate, Brazil</nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2002">2002</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Hereditary gingival fibromatosis (HGF) is a rare, autosomal dominant form of gingival overgrowth. Affected individuals have a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of the oral masticatory mucosa. Genetic loci for autosomal dominant forms of HGF have been localized to chromosome 2p21-p22 (HGF1) and chromosome 5q13-q22 (HGF2). To identify the gene responsible for HGF1, we extended genetic linkage studies to refine the chromosome 2p21-p22 candidate interval to ∼2.3 Mb. Development of an integrated physical and genetic map of the interval identified 16 genes. Sequencing of these genes, in affected and unaffected HGF1 family members, identified a mutation in the <italic>Son of sevenless–1</italic> (<italic>SOS1</italic>) gene in affected individuals. In this report, we describe the genomic structure of the <italic>SOS1</italic> gene and present evidence that insertion of a cytosine between nucleotides 126,142 and 126,143 in codon 1083 of the <italic>SOS1</italic> gene is responsible for HGF1. This insertion mutation, which segregates in a dominant manner over four generations, introduces a frameshift and creates a premature stop codon, abolishing four functionally important proline-rich SH3 binding domains normally present in the carboxyl-terminal region of the SOS1 protein. The resultant protein chimera contains the wild-type SOS1 protein for the N-terminal amino acids 1–1083 fused to a novel 22–amino acid carboxyl terminus. Similar SOS1 deletion constructs are functional in animal models, and a transgenic mouse construct with a comparable SOS1 chimera produces a phenotype with skin hypertrophy. Clarification of the functional role of this SOS1 mutant has implications for understanding other forms of gingival fibromatosis and corrective gingival-tissue management.</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 Hum Genet</journal-id><journal-id journal-id-type="publisher-id">AJHG</journal-id><journal-title>American Journal of Human Genetics</journal-title><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>The American Society of Human Genetics</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">11868160</article-id><article-id pub-id-type="pmc">379122</article-id><article-id pub-id-type="publisher-id">013589</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>A Mutation in the <italic>SOS1</italic> Gene Causes Hereditary Gingival Fibromatosis Type 1</article-title><alt-title><italic>SOS1</italic> Mutation Causes HGF1</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hart</surname><given-names>Thomas C.</given-names></name><xref ref-type="aff" rid="N0x97739c8.0x8be2520">1,2</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Yingze</given-names></name><xref ref-type="aff" rid="N0x97739c8.0x8be2520">1</xref></contrib><contrib contrib-type="author"><name><surname>Gorry</surname><given-names>Michael C.</given-names></name><xref ref-type="aff" rid="N0x97739c8.0x8be2520">1</xref></contrib><contrib contrib-type="author"><name><surname>Hart</surname><given-names>P. Suzanne</given-names></name><xref ref-type="aff" rid="N0x97739c8.0x8be2520">2</xref></contrib><contrib contrib-type="author"><name><surname>Cooper</surname><given-names>Margaret</given-names></name><xref ref-type="aff" rid="N0x97739c8.0x8be2520">1</xref></contrib><contrib contrib-type="author"><name><surname>Marazita</surname><given-names>Mary L.</given-names></name><xref ref-type="aff" rid="N0x97739c8.0x8be2520">1,2</xref></contrib><contrib contrib-type="author"><name><surname>Marks</surname><given-names>Jared M.</given-names></name><xref ref-type="aff" rid="N0x97739c8.0x8be2520">1</xref></contrib><contrib contrib-type="author"><name><surname>Cortelli</surname><given-names>Jose R.</given-names></name><xref ref-type="aff" rid="N0x97739c8.0x8be2520">3</xref></contrib><contrib contrib-type="author"><name><surname>Pallos</surname><given-names>Debora</given-names></name><xref ref-type="aff" rid="N0x97739c8.0x8be2520">3</xref></contrib></contrib-group><aff id="N0x97739c8.0x8be2520"><sup>1</sup>Center For Craniofacial and Dental Genetics, Division of Oral Biology and Pathology, University of Pittsburgh School of Dental Medicine, and<sup>2</sup>Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh; and<sup>3</sup>Department of Periodontics, School of Dentistry, University of Taubate, Taubate, Brazil</aff><author-notes><corresp>Address for correspondence and reprints: Dr. Thomas C. Hart, Center for Craniofacial and Dental Genetics, 614 Salk Hall, 3501 Terrace Street, Pittsburgh, PA 15261. E-mail: <email>hart@sdmgenetics.pitt.edu</email></corresp></author-notes><pub-date pub-type="ppub"><month>4</month><year>2002</year></pub-date><pub-date pub-type="epub"><day>26</day><month>2</month><year>2002</year></pub-date><volume>70</volume><issue>4</issue><fpage>943</fpage><lpage>954</lpage><history><date date-type="received"><day>29</day><month>11</month><year>2001</year></date><date date-type="accepted"><day>10</day><month>1</month><year>2002</year></date></history><copyright-statement>© 2002 by The American Society of Human Genetics. All rights reserved.</copyright-statement><copyright-year>2002</copyright-year><self-uri>11868160</self-uri><abstract><p>Hereditary gingival fibromatosis (HGF) is a rare, autosomal dominant form of gingival overgrowth. Affected individuals have a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of the oral masticatory mucosa. Genetic loci for autosomal dominant forms of HGF have been localized to chromosome 2p21-p22 (HGF1) and chromosome 5q13-q22 (HGF2). To identify the gene responsible for HGF1, we extended genetic linkage studies to refine the chromosome 2p21-p22 candidate interval to ∼2.3 Mb. Development of an integrated physical and genetic map of the interval identified 16 genes. Sequencing of these genes, in affected and unaffected HGF1 family members, identified a mutation in the <italic>Son of sevenless–1</italic> (<italic>SOS1</italic>) gene in affected individuals. In this report, we describe the genomic structure of the <italic>SOS1</italic> gene and present evidence that insertion of a cytosine between nucleotides 126,142 and 126,143 in codon 1083 of the <italic>SOS1</italic> gene is responsible for HGF1. This insertion mutation, which segregates in a dominant manner over four generations, introduces a frameshift and creates a premature stop codon, abolishing four functionally important proline-rich SH3 binding domains normally present in the carboxyl-terminal region of the SOS1 protein. The resultant protein chimera contains the wild-type SOS1 protein for the N-terminal amino acids 1–1083 fused to a novel 22–amino acid carboxyl terminus. Similar SOS1 deletion constructs are functional in animal models, and a transgenic mouse construct with a comparable SOS1 chimera produces a phenotype with skin hypertrophy. Clarification of the functional role of this SOS1 mutant has implications for understanding other forms of gingival fibromatosis and corrective gingival-tissue management.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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