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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Human Homeotic Transformation Resulting from Mutations in <italic>PLCB4</italic> and <italic>GNAI3</italic> Causes Auriculocondylar Syndrome</title><author><name sortKey="Rieder, Mark J" sort="Rieder, Mark J" uniqKey="Rieder M" first="Mark J." last="Rieder">Mark J. Rieder</name><affiliation><nlm:aff id="aff1">Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Green, Glenn E" sort="Green, Glenn E" uniqKey="Green G" first="Glenn E." last="Green">Glenn E. Green</name><affiliation><nlm:aff id="aff2">Department of Otolaryngology—Head & Neck Surgery, University of Michigan, Ann Arbor, MI 48109, USA</nlm:aff></affiliation></author><author><name sortKey="Park, Sarah S" sort="Park, Sarah S" uniqKey="Park S" first="Sarah S." last="Park">Sarah S. Park</name><affiliation><nlm:aff id="aff3">Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA</nlm:aff></affiliation></author><author><name sortKey="Stamper, Brendan D" sort="Stamper, Brendan D" uniqKey="Stamper B" first="Brendan D." last="Stamper">Brendan D. Stamper</name><affiliation><nlm:aff id="aff3">Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA</nlm:aff></affiliation></author><author><name sortKey="Gordon, Christopher T" sort="Gordon, Christopher T" uniqKey="Gordon C" first="Christopher T." last="Gordon">Christopher T. Gordon</name><affiliation><nlm:aff id="aff4">INSERM, U781, Hôpital Necker—Enfants Malades, 75743 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France, 75743</nlm:aff></affiliation></author><author><name sortKey="Johnson, Jason M" sort="Johnson, Jason M" uniqKey="Johnson J" first="Jason M." last="Johnson">Jason M. Johnson</name><affiliation><nlm:aff id="aff6">Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA</nlm:aff></affiliation></author><author><name sortKey="Cunniff, Christopher M" sort="Cunniff, Christopher M" uniqKey="Cunniff C" first="Christopher M." last="Cunniff">Christopher M. Cunniff</name><affiliation><nlm:aff id="aff7">Department of Pediatrics, University of Arizona, Tucson, AZ 85724, USA</nlm:aff></affiliation></author><author><name sortKey="Smith, Joshua D" sort="Smith, Joshua D" uniqKey="Smith J" first="Joshua D." last="Smith">Joshua D. Smith</name><affiliation><nlm:aff id="aff1">Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Emery, Sarah B" sort="Emery, Sarah B" uniqKey="Emery S" first="Sarah B." last="Emery">Sarah B. Emery</name><affiliation><nlm:aff id="aff2">Department of Otolaryngology—Head & Neck Surgery, University of Michigan, Ann Arbor, MI 48109, USA</nlm:aff></affiliation></author><author><name sortKey="Lyonnet, Stanislas" sort="Lyonnet, Stanislas" uniqKey="Lyonnet S" first="Stanislas" last="Lyonnet">Stanislas Lyonnet</name><affiliation><nlm:aff id="aff4">INSERM, U781, Hôpital Necker—Enfants Malades, 75743 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France, 75743</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">AP-HP, Département de Génétique, Hôpital Necker—Enfants Malades, 75743 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Amiel, Jeanne" sort="Amiel, Jeanne" uniqKey="Amiel J" first="Jeanne" last="Amiel">Jeanne Amiel</name><affiliation><nlm:aff id="aff4">INSERM, U781, Hôpital Necker—Enfants Malades, 75743 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France, 75743</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">AP-HP, Département de Génétique, Hôpital Necker—Enfants Malades, 75743 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Holder, Muriel" sort="Holder, Muriel" uniqKey="Holder M" first="Muriel" last="Holder">Muriel Holder</name><affiliation><nlm:aff id="aff9">Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU 59037 Lille, France</nlm:aff></affiliation></author><author><name sortKey="Heggie, Andrew A" sort="Heggie, Andrew A" uniqKey="Heggie A" first="Andrew A." last="Heggie">Andrew A. Heggie</name><affiliation><nlm:aff id="aff10">Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Melbourne, Victoria 3052, Australia</nlm:aff></affiliation></author><author><name sortKey="Bamshad, Michael J" sort="Bamshad, Michael J" uniqKey="Bamshad M" first="Michael J." last="Bamshad">Michael J. Bamshad</name><affiliation><nlm:aff id="aff1">Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Department of Pediatrics, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Nickerson, Deborah A" sort="Nickerson, Deborah A" uniqKey="Nickerson D" first="Deborah A." last="Nickerson">Deborah A. Nickerson</name><affiliation><nlm:aff id="aff1">Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Cox, Timothy C" sort="Cox, Timothy C" uniqKey="Cox T" first="Timothy C." last="Cox">Timothy C. Cox</name><affiliation><nlm:aff id="aff3">Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Department of Pediatrics, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Craniofacial Center, Seattle Children's Research Institute, Seattle, WA 98105, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff13">Department of Anatomy & Developmental Biology, Monash University, Clayton, Victoria 3800, Australia</nlm:aff></affiliation></author><author><name sortKey="Hing, Anne V" sort="Hing, Anne V" uniqKey="Hing A" first="Anne V." last="Hing">Anne V. Hing</name><affiliation><nlm:aff id="aff3">Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Department of Pediatrics, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Craniofacial Center, Seattle Children's Research Institute, Seattle, WA 98105, USA</nlm:aff></affiliation></author><author><name sortKey="Horst, Jeremy A" sort="Horst, Jeremy A" uniqKey="Horst J" first="Jeremy A." last="Horst">Jeremy A. Horst</name><affiliation><nlm:aff id="aff14">Division of Pediatric Dentistry, Department of Orofacial Sciences, UCSF, San Francisco, CA 94143, USA</nlm:aff></affiliation></author><author><name sortKey="Cunningham, Michael L" sort="Cunningham, Michael L" uniqKey="Cunningham M" first="Michael L." last="Cunningham">Michael L. Cunningham</name><affiliation><nlm:aff id="aff3">Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Department of Pediatrics, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Craniofacial Center, Seattle Children's Research Institute, Seattle, WA 98105, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22560091</idno><idno type="pmc">3376493</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376493</idno><idno type="RBID">PMC:3376493</idno><idno type="doi">10.1016/j.ajhg.2012.04.002</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">001198</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001198</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Human Homeotic Transformation Resulting from Mutations in <italic>PLCB4</italic> and <italic>GNAI3</italic> Causes Auriculocondylar Syndrome</title><author><name sortKey="Rieder, Mark J" sort="Rieder, Mark J" uniqKey="Rieder M" first="Mark J." last="Rieder">Mark J. Rieder</name><affiliation><nlm:aff id="aff1">Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Green, Glenn E" sort="Green, Glenn E" uniqKey="Green G" first="Glenn E." last="Green">Glenn E. Green</name><affiliation><nlm:aff id="aff2">Department of Otolaryngology—Head & Neck Surgery, University of Michigan, Ann Arbor, MI 48109, USA</nlm:aff></affiliation></author><author><name sortKey="Park, Sarah S" sort="Park, Sarah S" uniqKey="Park S" first="Sarah S." last="Park">Sarah S. Park</name><affiliation><nlm:aff id="aff3">Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA</nlm:aff></affiliation></author><author><name sortKey="Stamper, Brendan D" sort="Stamper, Brendan D" uniqKey="Stamper B" first="Brendan D." last="Stamper">Brendan D. Stamper</name><affiliation><nlm:aff id="aff3">Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA</nlm:aff></affiliation></author><author><name sortKey="Gordon, Christopher T" sort="Gordon, Christopher T" uniqKey="Gordon C" first="Christopher T." last="Gordon">Christopher T. Gordon</name><affiliation><nlm:aff id="aff4">INSERM, U781, Hôpital Necker—Enfants Malades, 75743 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France, 75743</nlm:aff></affiliation></author><author><name sortKey="Johnson, Jason M" sort="Johnson, Jason M" uniqKey="Johnson J" first="Jason M." last="Johnson">Jason M. Johnson</name><affiliation><nlm:aff id="aff6">Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA</nlm:aff></affiliation></author><author><name sortKey="Cunniff, Christopher M" sort="Cunniff, Christopher M" uniqKey="Cunniff C" first="Christopher M." last="Cunniff">Christopher M. Cunniff</name><affiliation><nlm:aff id="aff7">Department of Pediatrics, University of Arizona, Tucson, AZ 85724, USA</nlm:aff></affiliation></author><author><name sortKey="Smith, Joshua D" sort="Smith, Joshua D" uniqKey="Smith J" first="Joshua D." last="Smith">Joshua D. Smith</name><affiliation><nlm:aff id="aff1">Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Emery, Sarah B" sort="Emery, Sarah B" uniqKey="Emery S" first="Sarah B." last="Emery">Sarah B. Emery</name><affiliation><nlm:aff id="aff2">Department of Otolaryngology—Head & Neck Surgery, University of Michigan, Ann Arbor, MI 48109, USA</nlm:aff></affiliation></author><author><name sortKey="Lyonnet, Stanislas" sort="Lyonnet, Stanislas" uniqKey="Lyonnet S" first="Stanislas" last="Lyonnet">Stanislas Lyonnet</name><affiliation><nlm:aff id="aff4">INSERM, U781, Hôpital Necker—Enfants Malades, 75743 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France, 75743</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">AP-HP, Département de Génétique, Hôpital Necker—Enfants Malades, 75743 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Amiel, Jeanne" sort="Amiel, Jeanne" uniqKey="Amiel J" first="Jeanne" last="Amiel">Jeanne Amiel</name><affiliation><nlm:aff id="aff4">INSERM, U781, Hôpital Necker—Enfants Malades, 75743 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France, 75743</nlm:aff></affiliation><affiliation><nlm:aff id="aff8">AP-HP, Département de Génétique, Hôpital Necker—Enfants Malades, 75743 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Holder, Muriel" sort="Holder, Muriel" uniqKey="Holder M" first="Muriel" last="Holder">Muriel Holder</name><affiliation><nlm:aff id="aff9">Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU 59037 Lille, France</nlm:aff></affiliation></author><author><name sortKey="Heggie, Andrew A" sort="Heggie, Andrew A" uniqKey="Heggie A" first="Andrew A." last="Heggie">Andrew A. Heggie</name><affiliation><nlm:aff id="aff10">Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Melbourne, Victoria 3052, Australia</nlm:aff></affiliation></author><author><name sortKey="Bamshad, Michael J" sort="Bamshad, Michael J" uniqKey="Bamshad M" first="Michael J." last="Bamshad">Michael J. Bamshad</name><affiliation><nlm:aff id="aff1">Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Department of Pediatrics, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Nickerson, Deborah A" sort="Nickerson, Deborah A" uniqKey="Nickerson D" first="Deborah A." last="Nickerson">Deborah A. Nickerson</name><affiliation><nlm:aff id="aff1">Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation></author><author><name sortKey="Cox, Timothy C" sort="Cox, Timothy C" uniqKey="Cox T" first="Timothy C." last="Cox">Timothy C. Cox</name><affiliation><nlm:aff id="aff3">Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Department of Pediatrics, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Craniofacial Center, Seattle Children's Research Institute, Seattle, WA 98105, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff13">Department of Anatomy & Developmental Biology, Monash University, Clayton, Victoria 3800, Australia</nlm:aff></affiliation></author><author><name sortKey="Hing, Anne V" sort="Hing, Anne V" uniqKey="Hing A" first="Anne V." last="Hing">Anne V. Hing</name><affiliation><nlm:aff id="aff3">Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Department of Pediatrics, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Craniofacial Center, Seattle Children's Research Institute, Seattle, WA 98105, USA</nlm:aff></affiliation></author><author><name sortKey="Horst, Jeremy A" sort="Horst, Jeremy A" uniqKey="Horst J" first="Jeremy A." last="Horst">Jeremy A. Horst</name><affiliation><nlm:aff id="aff14">Division of Pediatric Dentistry, Department of Orofacial Sciences, UCSF, San Francisco, CA 94143, USA</nlm:aff></affiliation></author><author><name sortKey="Cunningham, Michael L" sort="Cunningham, Michael L" uniqKey="Cunningham M" first="Michael L." last="Cunningham">Michael L. Cunningham</name><affiliation><nlm:aff id="aff3">Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">Department of Pediatrics, University of Washington, Seattle, WA 98195, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff12">Craniofacial Center, Seattle Children's Research Institute, Seattle, WA 98105, USA</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="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Auriculocondylar syndrome (ACS) is a rare, autosomal-dominant craniofacial malformation syndrome characterized by variable micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic “question-mark” ear malformation. Careful phenotypic characterization of severely affected probands in our cohort suggested the presence of a mandibular patterning defect resulting in a maxillary phenotype (i.e., homeotic transformation). We used exome sequencing of five probands and identified two novel (exclusive to the patient and/or family studied) missense mutations in <italic>PLCB4</italic> and a shared mutation in <italic>GNAI3</italic> in two unrelated probands. In confirmatory studies, three additional novel <italic>PLCB4</italic> mutations were found in multigenerational ACS pedigrees. All mutations were confirmed by Sanger sequencing, were not present in more than 10,000 control chromosomes, and resulted in amino-acid substitutions located in highly conserved protein domains. Additionally, protein-structure modeling demonstrated that all ACS substitutions disrupt the catalytic sites of PLCB4 and GNAI3. We suggest that PLCB4 and GNAI3 are core signaling molecules of the endothelin-1-distal-less homeobox 5 and 6 (EDN1-DLX5/DLX6) pathway. Functional studies demonstrated a significant reduction in downstream <italic>DLX5</italic> and <italic>DLX6</italic> expression in ACS cases in assays using cultured osteoblasts from probands and controls. These results support the role of the previously implicated EDN1-DLX5/6 pathway in regulating mandibular specification in other species, which, when disrupted, results in a maxillary phenotype. This work defines the molecular basis of ACS as a homeotic transformation (mandible to maxilla) in humans.</p></div></front></TEI><pmc article-type="brief-report"><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="iso-abbrev">Am. J. Hum. Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22560091</article-id><article-id pub-id-type="pmc">3376493</article-id><article-id pub-id-type="publisher-id">AJHG1132</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2012.04.002</article-id><article-categories><subj-group subj-group-type="heading"><subject>Report</subject></subj-group></article-categories><title-group><article-title>A Human Homeotic Transformation Resulting from Mutations in <italic>PLCB4</italic> and <italic>GNAI3</italic> Causes Auriculocondylar Syndrome</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Rieder</surname><given-names>Mark J.</given-names></name><email>acs_rieder_cunningham@uw.edu</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Green</surname><given-names>Glenn E.</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Sarah S.</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Stamper</surname><given-names>Brendan D.</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Gordon</surname><given-names>Christopher T.</given-names></name><xref rid="aff4" ref-type="aff">4</xref><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Johnson</surname><given-names>Jason M.</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Cunniff</surname><given-names>Christopher M.</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Smith</surname><given-names>Joshua D.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Emery</surname><given-names>Sarah B.</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Lyonnet</surname><given-names>Stanislas</given-names></name><xref rid="aff4" ref-type="aff">4</xref><xref rid="aff5" ref-type="aff">5</xref><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Amiel</surname><given-names>Jeanne</given-names></name><xref rid="aff4" ref-type="aff">4</xref><xref rid="aff5" ref-type="aff">5</xref><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Holder</surname><given-names>Muriel</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Heggie</surname><given-names>Andrew A.</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Bamshad</surname><given-names>Michael J.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Nickerson</surname><given-names>Deborah A.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Cox</surname><given-names>Timothy C.</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff11" ref-type="aff">11</xref><xref rid="aff12" ref-type="aff">12</xref><xref rid="aff13" ref-type="aff">13</xref></contrib><contrib contrib-type="author"><name><surname>Hing</surname><given-names>Anne V.</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff11" ref-type="aff">11</xref><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>Horst</surname><given-names>Jeremy A.</given-names></name><xref rid="aff14" ref-type="aff">14</xref></contrib><contrib contrib-type="author"><name><surname>Cunningham</surname><given-names>Michael L.</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff11" ref-type="aff">11</xref><xref rid="aff12" ref-type="aff">12</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</aff><aff id="aff2"><label>2</label>Department of Otolaryngology—Head & Neck Surgery, University of Michigan, Ann Arbor, MI 48109, USA</aff><aff id="aff3"><label>3</label>Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA</aff><aff id="aff4"><label>4</label>INSERM, U781, Hôpital Necker—Enfants Malades, 75743 Paris, France</aff><aff id="aff5"><label>5</label>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France, 75743</aff><aff id="aff6"><label>6</label>Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA</aff><aff id="aff7"><label>7</label>Department of Pediatrics, University of Arizona, Tucson, AZ 85724, USA</aff><aff id="aff8"><label>8</label>AP-HP, Département de Génétique, Hôpital Necker—Enfants Malades, 75743 Paris, France</aff><aff id="aff9"><label>9</label>Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU 59037 Lille, France</aff><aff id="aff10"><label>10</label>Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Melbourne, Victoria 3052, Australia</aff><aff id="aff11"><label>11</label>Department of Pediatrics, University of Washington, Seattle, WA 98195, USA</aff><aff id="aff12"><label>12</label>Craniofacial Center, Seattle Children's Research Institute, Seattle, WA 98105, USA</aff><aff id="aff13"><label>13</label>Department of Anatomy & Developmental Biology, Monash University, Clayton, Victoria 3800, Australia</aff><aff id="aff14"><label>14</label>Division of Pediatric Dentistry, Department of Orofacial Sciences, UCSF, San Francisco, CA 94143, USA</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>acs_rieder_cunningham@uw.edu</email></corresp></author-notes><pub-date pub-type="ppub"><day>04</day><month>5</month><year>2012</year></pub-date><volume>90</volume><issue>5</issue><fpage>907</fpage><lpage>914</lpage><history><date date-type="received"><day>4</day><month>1</month><year>2012</year></date><date date-type="rev-recd"><day>10</day><month>2</month><year>2012</year></date><date date-type="accepted"><day>3</day><month>4</month><year>2012</year></date></history><permissions><copyright-statement>© 2012 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2012</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>Auriculocondylar syndrome (ACS) is a rare, autosomal-dominant craniofacial malformation syndrome characterized by variable micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic “question-mark” ear malformation. Careful phenotypic characterization of severely affected probands in our cohort suggested the presence of a mandibular patterning defect resulting in a maxillary phenotype (i.e., homeotic transformation). We used exome sequencing of five probands and identified two novel (exclusive to the patient and/or family studied) missense mutations in <italic>PLCB4</italic> and a shared mutation in <italic>GNAI3</italic> in two unrelated probands. In confirmatory studies, three additional novel <italic>PLCB4</italic> mutations were found in multigenerational ACS pedigrees. All mutations were confirmed by Sanger sequencing, were not present in more than 10,000 control chromosomes, and resulted in amino-acid substitutions located in highly conserved protein domains. Additionally, protein-structure modeling demonstrated that all ACS substitutions disrupt the catalytic sites of PLCB4 and GNAI3. We suggest that PLCB4 and GNAI3 are core signaling molecules of the endothelin-1-distal-less homeobox 5 and 6 (EDN1-DLX5/DLX6) pathway. Functional studies demonstrated a significant reduction in downstream <italic>DLX5</italic> and <italic>DLX6</italic> expression in ACS cases in assays using cultured osteoblasts from probands and controls. These results support the role of the previously implicated EDN1-DLX5/6 pathway in regulating mandibular specification in other species, which, when disrupted, results in a maxillary phenotype. This work defines the molecular basis of ACS as a homeotic transformation (mandible to maxilla) in humans.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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