SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1–SIX1–DNA complexes
Identifieur interne : 001073 ( Pmc/Corpus ); précédent : 001072; suivant : 001074SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1–SIX1–DNA complexes
Auteurs : Rainer G. Ruf ; Pin-Xian Xu ; Derek Silvius ; Edgar A. Otto ; Frank Beekmann ; Ulla T. Muerb ; Shrawan Kumar ; Thomas J. Neuhaus ; Markus J. Kemper ; Richard M. Raymond ; Patrick D. Brophy ; Jennifer Berkman ; Michael Gattas ; Valentine Hyland ; Eva-Maria Ruf ; Charles Schwartz ; Eugene H. Chang ; Richard J. H. Smith ; Constantine A. Stratakis ; Dominique Weil ; Christine Petit ; Friedhelm HildebrandtSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2004.
Abstract
Urinary tract malformations constitute the most frequent cause of chronic renal failure in the first two decades of life. Branchio-otic (BO) syndrome is an autosomal dominant developmental disorder characterized by hearing loss. In branchio-oto-renal (BOR) syndrome, malformations of the kidney or urinary tract are associated. Haploinsufficiency for the human gene
Url:
DOI: 10.1073/pnas.0308475101
PubMed: 15141091
PubMed Central: 419562
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PMC:419562Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1–SIX1–DNA complexes</title>
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<author><name sortKey="Kumar, Shrawan" sort="Kumar, Shrawan" uniqKey="Kumar S" first="Shrawan" last="Kumar">Shrawan Kumar</name>
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</affiliation>
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<author><name sortKey="Neuhaus, Thomas J" sort="Neuhaus, Thomas J" uniqKey="Neuhaus T" first="Thomas J." last="Neuhaus">Thomas J. Neuhaus</name>
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</affiliation>
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<author><name sortKey="Kemper, Markus J" sort="Kemper, Markus J" uniqKey="Kemper M" first="Markus J." last="Kemper">Markus J. Kemper</name>
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<author><name sortKey="Raymond, Richard M" sort="Raymond, Richard M" uniqKey="Raymond R" first="Richard M." last="Raymond">Richard M. Raymond</name>
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<author><name sortKey="Brophy, Patrick D" sort="Brophy, Patrick D" uniqKey="Brophy P" first="Patrick D." last="Brophy">Patrick D. Brophy</name>
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<author><name sortKey="Berkman, Jennifer" sort="Berkman, Jennifer" uniqKey="Berkman J" first="Jennifer" last="Berkman">Jennifer Berkman</name>
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<author><name sortKey="Gattas, Michael" sort="Gattas, Michael" uniqKey="Gattas M" first="Michael" last="Gattas">Michael Gattas</name>
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<author><name sortKey="Hyland, Valentine" sort="Hyland, Valentine" uniqKey="Hyland V" first="Valentine" last="Hyland">Valentine Hyland</name>
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<author><name sortKey="Ruf, Eva Maria" sort="Ruf, Eva Maria" uniqKey="Ruf E" first="Eva-Maria" last="Ruf">Eva-Maria Ruf</name>
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<author><name sortKey="Stratakis, Constantine A" sort="Stratakis, Constantine A" uniqKey="Stratakis C" first="Constantine A." last="Stratakis">Constantine A. Stratakis</name>
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<author><name sortKey="Weil, Dominique" sort="Weil, Dominique" uniqKey="Weil D" first="Dominique" last="Weil">Dominique Weil</name>
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<author><name sortKey="Petit, Christine" sort="Petit, Christine" uniqKey="Petit C" first="Christine" last="Petit">Christine Petit</name>
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<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="2004">2004</date>
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<front><div type="abstract" xml:lang="en"><p>Urinary tract malformations constitute the most frequent cause of chronic renal failure in the first two decades of life. Branchio-otic (BO) syndrome is an autosomal dominant developmental disorder characterized by hearing loss. In branchio-oto-renal (BOR) syndrome, malformations of the kidney or urinary tract are associated. Haploinsufficiency for the human gene <italic>EYA1</italic>
, a homologue of the <italic>Drosophila</italic>
gene <italic>eyes absent</italic>
(<italic>eya</italic>
), causes BOR and BO syndromes. We recently mapped a locus for BOR/BO syndrome (<italic>BOS3</italic>
) to human chromosome 14q23.1. Within the 33-megabase critical genetic interval, we located the <italic>SIX1</italic>
, <italic>SIX4</italic>
, and <italic>SIX6</italic>
genes, which act within a genetic network of <italic>EYA</italic>
and <italic>PAX</italic>
genes to regulate organogenesis. These genes, therefore, represented excellent candidate genes for <italic>BOS3</italic>
. By direct sequencing of exons, we identified three different <italic>SIX1</italic>
mutations in four BOR/BO kindreds, thus identifying <italic>SIX1</italic>
as a gene causing BOR and BO syndromes. To elucidate how these mutations cause disease, we analyzed the functional role of these <italic>SIX1</italic>
mutations with respect to protein–protein and protein–DNA interactions. We demonstrate that all three mutations are crucial for Eya1–Six1 interaction, and the two mutations within the homeodomain region are essential for specific Six1–DNA binding. Identification of <italic>SIX1</italic>
mutations as causing BOR/BO offers insights into the molecular basis of otic and renal developmental diseases in humans.</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>National Academy of Sciences</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">15141091</article-id>
<article-id pub-id-type="pmc">419562</article-id>
<article-id pub-id-type="publisher-id">1018090</article-id>
<article-id pub-id-type="doi">10.1073/pnas.0308475101</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject>
<subj-group><subject>Genetics</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1–SIX1–DNA complexes</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Ruf</surname>
<given-names>Rainer G.</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">a</xref>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">b</xref>
<xref ref-type="fn" rid="fn1">c</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Xu</surname>
<given-names>Pin-Xian</given-names>
</name>
<xref ref-type="fn" rid="fn1">c</xref>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">d</xref>
<xref ref-type="corresp" rid="cor1">e</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Silvius</surname>
<given-names>Derek</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">d</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Otto</surname>
<given-names>Edgar A.</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">a</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Beekmann</surname>
<given-names>Frank</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">a</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Muerb</surname>
<given-names>Ulla T.</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">a</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kumar</surname>
<given-names>Shrawan</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">f</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Neuhaus</surname>
<given-names>Thomas J.</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">g</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kemper</surname>
<given-names>Markus J.</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">g</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Raymond</surname>
<given-names>Richard M.</given-names>
<suffix>Jr.</suffix>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">a</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brophy</surname>
<given-names>Patrick D.</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">a</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Berkman</surname>
<given-names>Jennifer</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">h</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gattas</surname>
<given-names>Michael</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">h</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hyland</surname>
<given-names>Valentine</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">i</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ruf</surname>
<given-names>Eva-Maria</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">a</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schwartz</surname>
<given-names>Charles</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">j</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chang</surname>
<given-names>Eugene H.</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">k</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Smith</surname>
<given-names>Richard J. H.</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">k</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Stratakis</surname>
<given-names>Constantine A.</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">l</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Weil</surname>
<given-names>Dominique</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">m</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Petit</surname>
<given-names>Christine</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">m</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hildebrandt</surname>
<given-names>Friedhelm</given-names>
</name>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">a</xref>
<xref ref-type="corresp" rid="cor1">e</xref>
<xref ref-type="aff" rid="N0x96815a0.0xa1f2ed0">n</xref>
</contrib>
</contrib-group>
<aff id="N0x96815a0.0xa1f2ed0">Departments of<label>a</label>
Pediatrics and<label>n</label>
Human Genetics, University of Michigan, Ann Arbor, MI 48109;<label>b</label>
University Children's Hospital, D-40225 Düsseldorf, Germany;<label>d</label>
McLaughlin Institute for Biomedical Sciences, Great Falls, MT 59405;<label>f</label>
Department of Genetics, Center for Hereditary and Communication Disorders, Boys Town National Research Hospital, Omaha, NE 68131;<label>g</label>
Kinderspital, University Children's Hospital, 8032 Zurich, Switzerland;<label>h</label>
Queensland Clinical Genetics Service, Royal Children's Hospital, Southport QLD 4215, Australia;<label>i</label>
Molecular Genetics Laboratory, Queensland Health Pathology Service, and RCH Foundation Laboratory, Brisbane QLD 4029, Australia;<label>j</label>
Center for Molecular Studies, J. C. Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646;<label>k</label>
Interdepartmental Genetics Program and Department of Otolaryngology, University of Iowa, Iowa City, IA 52246;<label>l</label>
Section of Endocrinology and Genetics, DEB, National Institute of Child Health and Human Development, Rockville, MD 20847; and<label>m</label>
Institute Pasteur, Institut National de la Santé et de la Recherche Médicale, U587, 75015 Paris, France</aff>
<author-notes><fn id="cor1"><label>e</label>
<p> To whom correspondence may be addressed. E-mail: <email>fhilde@umich.edu</email>
or <email>pxu@po.mri.montana.edu</email>
. </p>
</fn>
<fn id="fn1"><label>c</label>
<p>R.G.R. and P.-X.X. contributed equally to this work.</p>
</fn>
<fn><p>Edited by Irving L. Weissman, Stanford University School of Medicine, Stanford, CA, and approved March 31, 2004</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>25</day>
<month>5</month>
<year>2004</year>
</pub-date>
<pub-date pub-type="epub"><day>12</day>
<month>5</month>
<year>2004</year>
</pub-date>
<volume>101</volume>
<issue>21</issue>
<fpage>8090</fpage>
<lpage>8095</lpage>
<history><date date-type="received"><day>19</day>
<month>12</month>
<year>2003</year>
</date>
</history>
<copyright-statement>Copyright © 2004, The National Academy of Sciences</copyright-statement>
<copyright-year>2004</copyright-year>
<abstract><p>Urinary tract malformations constitute the most frequent cause of chronic renal failure in the first two decades of life. Branchio-otic (BO) syndrome is an autosomal dominant developmental disorder characterized by hearing loss. In branchio-oto-renal (BOR) syndrome, malformations of the kidney or urinary tract are associated. Haploinsufficiency for the human gene <italic>EYA1</italic>
, a homologue of the <italic>Drosophila</italic>
gene <italic>eyes absent</italic>
(<italic>eya</italic>
), causes BOR and BO syndromes. We recently mapped a locus for BOR/BO syndrome (<italic>BOS3</italic>
) to human chromosome 14q23.1. Within the 33-megabase critical genetic interval, we located the <italic>SIX1</italic>
, <italic>SIX4</italic>
, and <italic>SIX6</italic>
genes, which act within a genetic network of <italic>EYA</italic>
and <italic>PAX</italic>
genes to regulate organogenesis. These genes, therefore, represented excellent candidate genes for <italic>BOS3</italic>
. By direct sequencing of exons, we identified three different <italic>SIX1</italic>
mutations in four BOR/BO kindreds, thus identifying <italic>SIX1</italic>
as a gene causing BOR and BO syndromes. To elucidate how these mutations cause disease, we analyzed the functional role of these <italic>SIX1</italic>
mutations with respect to protein–protein and protein–DNA interactions. We demonstrate that all three mutations are crucial for Eya1–Six1 interaction, and the two mutations within the homeodomain region are essential for specific Six1–DNA binding. Identification of <italic>SIX1</italic>
mutations as causing BOR/BO offers insights into the molecular basis of otic and renal developmental diseases in humans.</p>
</abstract>
</article-meta>
<notes><fn-group><fn><p>This paper was submitted directly (Track II) to the PNAS office.</p>
</fn>
<fn><p>Abbreviations: BOR, branchio-oto-renal syndrome; BO, branchio-otic syndrome; Eya1D, Eya1 domain; β-gal, β-galactosidase; CMV, cytomegalovirus; HD, homeodomain; SD, six domain.</p>
</fn>
</fn-group>
</notes>
</front>
</pmc>
</record>
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