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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mutations in the human GlyT2 gene define a presynaptic component of human startle disease</title><author><name sortKey="Rees, Mark I" sort="Rees, Mark I" uniqKey="Rees M" first="Mark I." last="Rees">Mark I. Rees</name><affiliation><nlm:aff id="A1">School of Medicine, University of Wales Swansea, Singleton Park, West Glamorgan SA2 8PP, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Dept. of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Harvey, Kirsten" sort="Harvey, Kirsten" uniqKey="Harvey K" first="Kirsten" last="Harvey">Kirsten Harvey</name><affiliation><nlm:aff id="A2">Dept. of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK</nlm:aff></affiliation></author><author><name sortKey="Pearce, Brian R" sort="Pearce, Brian R" uniqKey="Pearce B" first="Brian R." last="Pearce">Brian R. Pearce</name><affiliation><nlm:aff id="A2">Dept. of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK</nlm:aff></affiliation></author><author><name sortKey="Chung, Seo Kyung" sort="Chung, Seo Kyung" uniqKey="Chung S" first="Seo-Kyung" last="Chung">Seo-Kyung Chung</name><affiliation><nlm:aff id="A1">School of Medicine, University of Wales Swansea, Singleton Park, West Glamorgan SA2 8PP, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Dept. of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Duguid, Ian C" sort="Duguid, Ian C" uniqKey="Duguid I" first="Ian C." last="Duguid">Ian C. Duguid</name><affiliation><nlm:aff id="A4">Dept. of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Thomas, Philip" sort="Thomas, Philip" uniqKey="Thomas P" first="Philip" last="Thomas">Philip Thomas</name><affiliation><nlm:aff id="A4">Dept. of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Beatty, Sarah" sort="Beatty, Sarah" uniqKey="Beatty S" first="Sarah" last="Beatty">Sarah Beatty</name><affiliation><nlm:aff id="A3">Dept. of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Graham, Gail E" sort="Graham, Gail E" uniqKey="Graham G" first="Gail E." last="Graham">Gail E. Graham</name><affiliation><nlm:aff id="A5">Dept. of Genetics, Children’s Hospital of Eastern Ontario, 401 Smyth Rd, Ontario K1H 8L1, Canada</nlm:aff></affiliation></author><author><name sortKey="Armstrong, Linlea" sort="Armstrong, Linlea" uniqKey="Armstrong L" first="Linlea" last="Armstrong">Linlea Armstrong</name><affiliation><nlm:aff id="A6">Dept. of Medical Genetics, Children’s and Women’s Health Centre of British Columbia, 4500 Oak Street, Vancouver, British Columbia V6H 3N1, Canada</nlm:aff></affiliation></author><author><name sortKey="Shiang, Rita" sort="Shiang, Rita" uniqKey="Shiang R" first="Rita" last="Shiang">Rita Shiang</name><affiliation><nlm:aff id="A7">Dept. of Human Genetics, Virginia Commonwealth University Medical Center, P.O. Box 980033, Richmond, VA 23298-0033, USA</nlm:aff></affiliation></author><author><name sortKey="Abbott, Kim J" sort="Abbott, Kim J" uniqKey="Abbott K" first="Kim J." last="Abbott">Kim J. Abbott</name><affiliation><nlm:aff id="A8">Women’s and Children’s Hospital, 72 King William Road, Adelaide, Australia</nlm:aff></affiliation></author><author><name sortKey="Zuberi, Sameer M" sort="Zuberi, Sameer M" uniqKey="Zuberi S" first="Sameer M." last="Zuberi">Sameer M. Zuberi</name><affiliation><nlm:aff id="A9">Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, G3 8SJ, UK</nlm:aff></affiliation></author><author><name sortKey="Stephenson, John B P" sort="Stephenson, John B P" uniqKey="Stephenson J" first="John B. P." last="Stephenson">John B. P. Stephenson</name><affiliation><nlm:aff id="A9">Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, G3 8SJ, UK</nlm:aff></affiliation></author><author><name sortKey="Owen, Michael J" sort="Owen, Michael J" uniqKey="Owen M" first="Michael J." last="Owen">Michael J. Owen</name><affiliation><nlm:aff id="A10">Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK</nlm:aff></affiliation></author><author><name sortKey="Tijssen, Marina A J" sort="Tijssen, Marina A J" uniqKey="Tijssen M" first="Marina A. J." last="Tijssen">Marina A. J. Tijssen</name><affiliation><nlm:aff id="A11">Dept. of Neurology, Academic Medical Centre, University of Amsterdam, PO BOX 22660, 1100 DD Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Den Maagdenberg, Arn M J M" sort="Van Den Maagdenberg, Arn M J M" uniqKey="Van Den Maagdenberg A" first="Arn M. J. M." last="Van Den Maagdenberg">Arn M. J. M. Van Den Maagdenberg</name><affiliation><nlm:aff id="A12">Dept. of Neurology and Dept. of Human Genetics, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Smart, Trevor G" sort="Smart, Trevor G" uniqKey="Smart T" first="Trevor G." last="Smart">Trevor G. Smart</name><affiliation><nlm:aff id="A4">Dept. of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Supplisson, Stephane" sort="Supplisson, Stephane" uniqKey="Supplisson S" first="Stéphane" last="Supplisson">Stéphane Supplisson</name><affiliation><nlm:aff id="A13">Laboratoire de Neurobiologie, CNRS UMR8544, Ecole Normale Supérieure, 46 Rue d’Ulm, 75005 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Harvey, Robert J" sort="Harvey, Robert J" uniqKey="Harvey R" first="Robert J." last="Harvey">Robert J. Harvey</name><affiliation><nlm:aff id="A2">Dept. of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">16751771</idno><idno type="pmc">3204411</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204411</idno><idno type="RBID">PMC:3204411</idno><idno type="doi">10.1038/ng1814</idno><date when="2006">2006</date><idno type="wicri:Area/Pmc/Corpus">002123</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002123</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutations in the human GlyT2 gene define a presynaptic component of human startle disease</title><author><name sortKey="Rees, Mark I" sort="Rees, Mark I" uniqKey="Rees M" first="Mark I." last="Rees">Mark I. Rees</name><affiliation><nlm:aff id="A1">School of Medicine, University of Wales Swansea, Singleton Park, West Glamorgan SA2 8PP, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Dept. of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Harvey, Kirsten" sort="Harvey, Kirsten" uniqKey="Harvey K" first="Kirsten" last="Harvey">Kirsten Harvey</name><affiliation><nlm:aff id="A2">Dept. of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK</nlm:aff></affiliation></author><author><name sortKey="Pearce, Brian R" sort="Pearce, Brian R" uniqKey="Pearce B" first="Brian R." last="Pearce">Brian R. Pearce</name><affiliation><nlm:aff id="A2">Dept. of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK</nlm:aff></affiliation></author><author><name sortKey="Chung, Seo Kyung" sort="Chung, Seo Kyung" uniqKey="Chung S" first="Seo-Kyung" last="Chung">Seo-Kyung Chung</name><affiliation><nlm:aff id="A1">School of Medicine, University of Wales Swansea, Singleton Park, West Glamorgan SA2 8PP, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Dept. of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Duguid, Ian C" sort="Duguid, Ian C" uniqKey="Duguid I" first="Ian C." last="Duguid">Ian C. Duguid</name><affiliation><nlm:aff id="A4">Dept. of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Thomas, Philip" sort="Thomas, Philip" uniqKey="Thomas P" first="Philip" last="Thomas">Philip Thomas</name><affiliation><nlm:aff id="A4">Dept. of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Beatty, Sarah" sort="Beatty, Sarah" uniqKey="Beatty S" first="Sarah" last="Beatty">Sarah Beatty</name><affiliation><nlm:aff id="A3">Dept. of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, New Zealand</nlm:aff></affiliation></author><author><name sortKey="Graham, Gail E" sort="Graham, Gail E" uniqKey="Graham G" first="Gail E." last="Graham">Gail E. Graham</name><affiliation><nlm:aff id="A5">Dept. of Genetics, Children’s Hospital of Eastern Ontario, 401 Smyth Rd, Ontario K1H 8L1, Canada</nlm:aff></affiliation></author><author><name sortKey="Armstrong, Linlea" sort="Armstrong, Linlea" uniqKey="Armstrong L" first="Linlea" last="Armstrong">Linlea Armstrong</name><affiliation><nlm:aff id="A6">Dept. of Medical Genetics, Children’s and Women’s Health Centre of British Columbia, 4500 Oak Street, Vancouver, British Columbia V6H 3N1, Canada</nlm:aff></affiliation></author><author><name sortKey="Shiang, Rita" sort="Shiang, Rita" uniqKey="Shiang R" first="Rita" last="Shiang">Rita Shiang</name><affiliation><nlm:aff id="A7">Dept. of Human Genetics, Virginia Commonwealth University Medical Center, P.O. Box 980033, Richmond, VA 23298-0033, USA</nlm:aff></affiliation></author><author><name sortKey="Abbott, Kim J" sort="Abbott, Kim J" uniqKey="Abbott K" first="Kim J." last="Abbott">Kim J. Abbott</name><affiliation><nlm:aff id="A8">Women’s and Children’s Hospital, 72 King William Road, Adelaide, Australia</nlm:aff></affiliation></author><author><name sortKey="Zuberi, Sameer M" sort="Zuberi, Sameer M" uniqKey="Zuberi S" first="Sameer M." last="Zuberi">Sameer M. Zuberi</name><affiliation><nlm:aff id="A9">Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, G3 8SJ, UK</nlm:aff></affiliation></author><author><name sortKey="Stephenson, John B P" sort="Stephenson, John B P" uniqKey="Stephenson J" first="John B. P." last="Stephenson">John B. P. Stephenson</name><affiliation><nlm:aff id="A9">Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, G3 8SJ, UK</nlm:aff></affiliation></author><author><name sortKey="Owen, Michael J" sort="Owen, Michael J" uniqKey="Owen M" first="Michael J." last="Owen">Michael J. Owen</name><affiliation><nlm:aff id="A10">Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK</nlm:aff></affiliation></author><author><name sortKey="Tijssen, Marina A J" sort="Tijssen, Marina A J" uniqKey="Tijssen M" first="Marina A. J." last="Tijssen">Marina A. J. Tijssen</name><affiliation><nlm:aff id="A11">Dept. of Neurology, Academic Medical Centre, University of Amsterdam, PO BOX 22660, 1100 DD Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Den Maagdenberg, Arn M J M" sort="Van Den Maagdenberg, Arn M J M" uniqKey="Van Den Maagdenberg A" first="Arn M. J. M." last="Van Den Maagdenberg">Arn M. J. M. Van Den Maagdenberg</name><affiliation><nlm:aff id="A12">Dept. of Neurology and Dept. of Human Genetics, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Smart, Trevor G" sort="Smart, Trevor G" uniqKey="Smart T" first="Trevor G." last="Smart">Trevor G. Smart</name><affiliation><nlm:aff id="A4">Dept. of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Supplisson, Stephane" sort="Supplisson, Stephane" uniqKey="Supplisson S" first="Stéphane" last="Supplisson">Stéphane Supplisson</name><affiliation><nlm:aff id="A13">Laboratoire de Neurobiologie, CNRS UMR8544, Ecole Normale Supérieure, 46 Rue d’Ulm, 75005 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Harvey, Robert J" sort="Harvey, Robert J" uniqKey="Harvey R" first="Robert J." last="Harvey">Robert J. Harvey</name><affiliation><nlm:aff id="A2">Dept. of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK</nlm:aff></affiliation></author></analytic><series><title level="j">Nature genetics</title><idno type="ISSN">1061-4036</idno><idno type="eISSN">1546-1718</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 id="P2">Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) α1 subunit (<italic>GLRA1</italic>)<sup><xref ref-type="bibr" rid="R1">1</xref>-<xref ref-type="bibr" rid="R3">3</xref></sup>. Genetic heterogeneity has been confirmed in isolated sporadic cases with mutations in other postsynaptic glycinergic proteins including the GlyR β subunit (<italic>GLRB</italic>)<sup><xref ref-type="bibr" rid="R4">4</xref></sup>, gephyrin (<italic>GPHN</italic>)<sup><xref ref-type="bibr" rid="R5">5</xref></sup> and RhoGEF collybistin (<italic>ARHGEF9</italic>)<sup><xref ref-type="bibr" rid="R6">6</xref></sup>. However, many sporadic patients diagnosed with hyperekplexia do not carry mutations in these genes<sup><xref ref-type="bibr" rid="R2">2</xref>-<xref ref-type="bibr" rid="R7">7</xref></sup>. Here we reveal that missense, nonsense and frameshift mutations in the presynaptic glycine transporter 2 (GlyT2) gene (<italic>SLC6A5</italic>)<sup><xref ref-type="bibr" rid="R8">8</xref></sup> also cause hyperekplexia. Patients harbouring mutations in <italic>SLC6A5</italic> presented with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnoea episodes. GlyT2 mutations result in defective subcellular localisation and/or decreased glycine uptake, with selected mutations affecting predicted glycine and Na<sup>+</sup> binding sites. Our results demonstrate that <italic>SLC6A5</italic> is a major gene for hyperekplexia and define the first neurological disorder linked to mutations in a Na<sup>+</sup>/Cl<sup>−</sup>-dependent transporter for a classical fast neurotransmitter. By analogy, we suggest that in other human disorders where defects in postsynaptic receptors have been identified, similar symptoms could result from defects in the cognate presynaptic neurotransmitter transporter.</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>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9216904</journal-id><journal-id journal-id-type="pubmed-jr-id">2419</journal-id><journal-id journal-id-type="nlm-ta">Nat Genet</journal-id><journal-id journal-id-type="iso-abbrev">Nat. Genet.</journal-id><journal-title-group><journal-title>Nature genetics</journal-title></journal-title-group><issn pub-type="ppub">1061-4036</issn><issn pub-type="epub">1546-1718</issn></journal-meta><article-meta><article-id pub-id-type="pmid">16751771</article-id><article-id pub-id-type="pmc">3204411</article-id><article-id pub-id-type="doi">10.1038/ng1814</article-id><article-id pub-id-type="manuscript">UKMS27750</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Mutations in the human GlyT2 gene define a presynaptic component of human startle disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Rees</surname><given-names>Mark I.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Harvey</surname><given-names>Kirsten</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Pearce</surname><given-names>Brian R.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Chung</surname><given-names>Seo-Kyung</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Duguid</surname><given-names>Ian C.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Thomas</surname><given-names>Philip</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Beatty</surname><given-names>Sarah</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Graham</surname><given-names>Gail E.</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Armstrong</surname><given-names>Linlea</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Shiang</surname><given-names>Rita</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Abbott</surname><given-names>Kim J.</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Zuberi</surname><given-names>Sameer M.</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Stephenson</surname><given-names>John B.P.</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Owen</surname><given-names>Michael J.</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Tijssen</surname><given-names>Marina A.J.</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>van den Maagdenberg</surname><given-names>Arn M.J.M.</given-names></name><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Smart</surname><given-names>Trevor G.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Supplisson</surname><given-names>Stéphane</given-names></name><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Harvey</surname><given-names>Robert J.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib></contrib-group><aff id="A1"><label>1</label>School of Medicine, University of Wales Swansea, Singleton Park, West Glamorgan SA2 8PP, UK</aff><aff id="A2"><label>2</label>Dept. of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK</aff><aff id="A3"><label>3</label>Dept. of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, New Zealand</aff><aff id="A4"><label>4</label>Dept. of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK</aff><aff id="A5"><label>5</label>Dept. of Genetics, Children’s Hospital of Eastern Ontario, 401 Smyth Rd, Ontario K1H 8L1, Canada</aff><aff id="A6"><label>6</label>Dept. of Medical Genetics, Children’s and Women’s Health Centre of British Columbia, 4500 Oak Street, Vancouver, British Columbia V6H 3N1, Canada</aff><aff id="A7"><label>7</label>Dept. of Human Genetics, Virginia Commonwealth University Medical Center, P.O. Box 980033, Richmond, VA 23298-0033, USA</aff><aff id="A8"><label>8</label>Women’s and Children’s Hospital, 72 King William Road, Adelaide, Australia</aff><aff id="A9"><label>9</label>Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, G3 8SJ, UK</aff><aff id="A10"><label>10</label>Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK</aff><aff id="A11"><label>11</label>Dept. of Neurology, Academic Medical Centre, University of Amsterdam, PO BOX 22660, 1100 DD Amsterdam, The Netherlands</aff><aff id="A12"><label>12</label>Dept. of Neurology and Dept. of Human Genetics, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands</aff><aff id="A13"><label>13</label>Laboratoire de Neurobiologie, CNRS UMR8544, Ecole Normale Supérieure, 46 Rue d’Ulm, 75005 Paris, France</aff><author-notes><corresp id="CR1">Correspondence and requests for materials (subject to a Material Transfer Agreement) should be addressed to R.J.H. (<email>robert.harvey@pharmacy.ac.uk</email>) or M.I.R. (<email>m.i.rees@swansea.ac.uk</email>).</corresp><fn fn-type="equal" id="FN1"><label>†</label><p id="P1">these authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>22</day><month>9</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>04</day><month>6</month><year>2006</year></pub-date><pub-date pub-type="ppub"><month>7</month><year>2006</year></pub-date><pub-date pub-type="pmc-release"><day>31</day><month>10</month><year>2011</year></pub-date><volume>38</volume><issue>7</issue><fpage>801</fpage><lpage>806</lpage><abstract><p id="P2">Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) α1 subunit (<italic>GLRA1</italic>)<sup><xref ref-type="bibr" rid="R1">1</xref>-<xref ref-type="bibr" rid="R3">3</xref></sup>. Genetic heterogeneity has been confirmed in isolated sporadic cases with mutations in other postsynaptic glycinergic proteins including the GlyR β subunit (<italic>GLRB</italic>)<sup><xref ref-type="bibr" rid="R4">4</xref></sup>, gephyrin (<italic>GPHN</italic>)<sup><xref ref-type="bibr" rid="R5">5</xref></sup> and RhoGEF collybistin (<italic>ARHGEF9</italic>)<sup><xref ref-type="bibr" rid="R6">6</xref></sup>. However, many sporadic patients diagnosed with hyperekplexia do not carry mutations in these genes<sup><xref ref-type="bibr" rid="R2">2</xref>-<xref ref-type="bibr" rid="R7">7</xref></sup>. Here we reveal that missense, nonsense and frameshift mutations in the presynaptic glycine transporter 2 (GlyT2) gene (<italic>SLC6A5</italic>)<sup><xref ref-type="bibr" rid="R8">8</xref></sup> also cause hyperekplexia. Patients harbouring mutations in <italic>SLC6A5</italic> presented with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnoea episodes. GlyT2 mutations result in defective subcellular localisation and/or decreased glycine uptake, with selected mutations affecting predicted glycine and Na<sup>+</sup> binding sites. Our results demonstrate that <italic>SLC6A5</italic> is a major gene for hyperekplexia and define the first neurological disorder linked to mutations in a Na<sup>+</sup>/Cl<sup>−</sup>-dependent transporter for a classical fast neurotransmitter. By analogy, we suggest that in other human disorders where defects in postsynaptic receptors have been identified, similar symptoms could result from defects in the cognate presynaptic neurotransmitter transporter.</p></abstract><funding-group><award-group><funding-source country="United Kingdom">Medical Research Council : </funding-source><award-id>G0601585(79887) || MRC_</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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