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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Homozygous Mutation in Human <italic>PRICKLE1</italic> Causes an Autosomal-Recessive Progressive Myoclonus Epilepsy-Ataxia Syndrome</title><author><name sortKey="Bassuk, Alexander G" sort="Bassuk, Alexander G" uniqKey="Bassuk A" first="Alexander G." last="Bassuk">Alexander G. Bassuk</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Wallace, Robyn H" sort="Wallace, Robyn H" uniqKey="Wallace R" first="Robyn H." last="Wallace">Robyn H. Wallace</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Buhr, Aimee" sort="Buhr, Aimee" uniqKey="Buhr A" first="Aimee" last="Buhr">Aimee Buhr</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Buller, Andrew R" sort="Buller, Andrew R" uniqKey="Buller A" first="Andrew R." last="Buller">Andrew R. Buller</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Afawi, Zaid" sort="Afawi, Zaid" uniqKey="Afawi Z" first="Zaid" last="Afawi">Zaid Afawi</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Shimojo, Masahito" sort="Shimojo, Masahito" uniqKey="Shimojo M" first="Masahito" last="Shimojo">Masahito Shimojo</name><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author><author><name sortKey="Miyata, Shingo" sort="Miyata, Shingo" uniqKey="Miyata S" first="Shingo" last="Miyata">Shingo Miyata</name><affiliation><nlm:aff id="aff10"></nlm:aff></affiliation></author><author><name sortKey="Chen, Shan" sort="Chen, Shan" uniqKey="Chen S" first="Shan" last="Chen">Shan Chen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Gonzalez Alegre, Pedro" sort="Gonzalez Alegre, Pedro" uniqKey="Gonzalez Alegre P" first="Pedro" last="Gonzalez-Alegre">Pedro Gonzalez-Alegre</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Griesbach, Hilary L" sort="Griesbach, Hilary L" uniqKey="Griesbach H" first="Hilary L." last="Griesbach">Hilary L. Griesbach</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Wu, Shu" sort="Wu, Shu" uniqKey="Wu S" first="Shu" last="Wu">Shu Wu</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Nashelsky, Marcus" sort="Nashelsky, Marcus" uniqKey="Nashelsky M" first="Marcus" last="Nashelsky">Marcus Nashelsky</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Vladar, Eszter K" sort="Vladar, Eszter K" uniqKey="Vladar E" first="Eszter K." last="Vladar">Eszter K. Vladar</name><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"></nlm:aff></affiliation></author><author><name sortKey="Antic, Dragana" sort="Antic, Dragana" uniqKey="Antic D" first="Dragana" last="Antic">Dragana Antic</name><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"></nlm:aff></affiliation></author><author><name sortKey="Ferguson, Polly J" sort="Ferguson, Polly J" uniqKey="Ferguson P" first="Polly J." last="Ferguson">Polly J. Ferguson</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Cirak, Sebahattin" sort="Cirak, Sebahattin" uniqKey="Cirak S" first="Sebahattin" last="Cirak">Sebahattin Cirak</name><affiliation><nlm:aff id="aff16"></nlm:aff></affiliation></author><author><name sortKey="Voit, Thomas" sort="Voit, Thomas" uniqKey="Voit T" first="Thomas" last="Voit">Thomas Voit</name><affiliation><nlm:aff id="aff17"></nlm:aff></affiliation></author><author><name sortKey="Scott, Matthew P" sort="Scott, Matthew P" uniqKey="Scott M" first="Matthew P." last="Scott">Matthew P. Scott</name><affiliation><nlm:aff id="aff12"></nlm:aff></affiliation><affiliation><nlm:aff id="aff13"></nlm:aff></affiliation><affiliation><nlm:aff id="aff14"></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"></nlm:aff></affiliation></author><author><name sortKey="Axelrod, Jeffrey D" sort="Axelrod, Jeffrey D" uniqKey="Axelrod J" first="Jeffrey D." last="Axelrod">Jeffrey D. Axelrod</name><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation></author><author><name sortKey="Gurnett, Christina" sort="Gurnett, Christina" uniqKey="Gurnett C" first="Christina" last="Gurnett">Christina Gurnett</name><affiliation><nlm:aff id="aff18"></nlm:aff></affiliation></author><author><name sortKey="Daoud, Azhar S" sort="Daoud, Azhar S" uniqKey="Daoud A" first="Azhar S." last="Daoud">Azhar S. Daoud</name><affiliation><nlm:aff id="aff19"></nlm:aff></affiliation></author><author><name sortKey="Kivity, Sara" sort="Kivity, Sara" uniqKey="Kivity S" first="Sara" last="Kivity">Sara Kivity</name><affiliation><nlm:aff id="aff20"></nlm:aff></affiliation></author><author><name sortKey="Neufeld, Miriam Y" sort="Neufeld, Miriam Y" uniqKey="Neufeld M" first="Miriam Y." last="Neufeld">Miriam Y. Neufeld</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Mazarib, Aziz" sort="Mazarib, Aziz" uniqKey="Mazarib A" first="Aziz" last="Mazarib">Aziz Mazarib</name><affiliation><nlm:aff id="aff22"></nlm:aff></affiliation></author><author><name sortKey="Straussberg, Rachel" sort="Straussberg, Rachel" uniqKey="Straussberg R" first="Rachel" last="Straussberg">Rachel Straussberg</name><affiliation><nlm:aff id="aff21"></nlm:aff></affiliation></author><author><name sortKey="Walid, Simri" sort="Walid, Simri" uniqKey="Walid S" first="Simri" last="Walid">Simri Walid</name><affiliation><nlm:aff id="aff23"></nlm:aff></affiliation></author><author><name sortKey="Korczyn, Amos D" sort="Korczyn, Amos D" uniqKey="Korczyn A" first="Amos D." last="Korczyn">Amos D. Korczyn</name><affiliation><nlm:aff id="aff24"></nlm:aff></affiliation></author><author><name sortKey="Slusarski, Diane C" sort="Slusarski, Diane C" uniqKey="Slusarski D" first="Diane C." last="Slusarski">Diane C. Slusarski</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Berkovic, Samuel F" sort="Berkovic, Samuel F" uniqKey="Berkovic S" first="Samuel F." last="Berkovic">Samuel F. Berkovic</name><affiliation><nlm:aff id="aff25"></nlm:aff></affiliation></author><author><name sortKey="El Shanti, Hatem I" sort="El Shanti, Hatem I" uniqKey="El Shanti H" first="Hatem I." last="El-Shanti">Hatem I. El-Shanti</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation><nlm:aff id="aff26"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">18976727</idno><idno type="pmc">2668041</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668041</idno><idno type="RBID">PMC:2668041</idno><idno type="doi">10.1016/j.ajhg.2008.10.003</idno><date when="2008">2008</date><idno type="wicri:Area/Pmc/Corpus">001704</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001704</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Homozygous Mutation in Human <italic>PRICKLE1</italic> Causes an Autosomal-Recessive Progressive Myoclonus Epilepsy-Ataxia Syndrome</title><author><name sortKey="Bassuk, Alexander G" sort="Bassuk, Alexander G" uniqKey="Bassuk A" first="Alexander G." last="Bassuk">Alexander G. Bassuk</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Wallace, Robyn H" sort="Wallace, Robyn H" uniqKey="Wallace R" first="Robyn H." last="Wallace">Robyn H. Wallace</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Buhr, Aimee" sort="Buhr, Aimee" uniqKey="Buhr A" first="Aimee" last="Buhr">Aimee Buhr</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Buller, Andrew R" sort="Buller, Andrew R" uniqKey="Buller A" first="Andrew R." last="Buller">Andrew R. Buller</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Afawi, Zaid" sort="Afawi, Zaid" uniqKey="Afawi Z" first="Zaid" last="Afawi">Zaid Afawi</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Shimojo, Masahito" sort="Shimojo, Masahito" uniqKey="Shimojo M" first="Masahito" last="Shimojo">Masahito Shimojo</name><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author><author><name sortKey="Miyata, Shingo" sort="Miyata, Shingo" uniqKey="Miyata S" first="Shingo" last="Miyata">Shingo Miyata</name><affiliation><nlm:aff id="aff10"></nlm:aff></affiliation></author><author><name sortKey="Chen, Shan" sort="Chen, Shan" uniqKey="Chen S" first="Shan" last="Chen">Shan Chen</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Gonzalez Alegre, Pedro" sort="Gonzalez Alegre, Pedro" uniqKey="Gonzalez Alegre P" first="Pedro" last="Gonzalez-Alegre">Pedro Gonzalez-Alegre</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Griesbach, Hilary L" sort="Griesbach, Hilary L" uniqKey="Griesbach H" first="Hilary L." last="Griesbach">Hilary L. Griesbach</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Wu, Shu" sort="Wu, Shu" uniqKey="Wu S" first="Shu" last="Wu">Shu Wu</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Nashelsky, Marcus" sort="Nashelsky, Marcus" uniqKey="Nashelsky M" first="Marcus" last="Nashelsky">Marcus Nashelsky</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Vladar, Eszter K" sort="Vladar, Eszter K" uniqKey="Vladar E" first="Eszter K." last="Vladar">Eszter K. Vladar</name><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"></nlm:aff></affiliation></author><author><name sortKey="Antic, Dragana" sort="Antic, Dragana" uniqKey="Antic D" first="Dragana" last="Antic">Dragana Antic</name><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"></nlm:aff></affiliation></author><author><name sortKey="Ferguson, Polly J" sort="Ferguson, Polly J" uniqKey="Ferguson P" first="Polly J." last="Ferguson">Polly J. Ferguson</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Cirak, Sebahattin" sort="Cirak, Sebahattin" uniqKey="Cirak S" first="Sebahattin" last="Cirak">Sebahattin Cirak</name><affiliation><nlm:aff id="aff16"></nlm:aff></affiliation></author><author><name sortKey="Voit, Thomas" sort="Voit, Thomas" uniqKey="Voit T" first="Thomas" last="Voit">Thomas Voit</name><affiliation><nlm:aff id="aff17"></nlm:aff></affiliation></author><author><name sortKey="Scott, Matthew P" sort="Scott, Matthew P" uniqKey="Scott M" first="Matthew P." last="Scott">Matthew P. Scott</name><affiliation><nlm:aff id="aff12"></nlm:aff></affiliation><affiliation><nlm:aff id="aff13"></nlm:aff></affiliation><affiliation><nlm:aff id="aff14"></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"></nlm:aff></affiliation></author><author><name sortKey="Axelrod, Jeffrey D" sort="Axelrod, Jeffrey D" uniqKey="Axelrod J" first="Jeffrey D." last="Axelrod">Jeffrey D. Axelrod</name><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation></author><author><name sortKey="Gurnett, Christina" sort="Gurnett, Christina" uniqKey="Gurnett C" first="Christina" last="Gurnett">Christina Gurnett</name><affiliation><nlm:aff id="aff18"></nlm:aff></affiliation></author><author><name sortKey="Daoud, Azhar S" sort="Daoud, Azhar S" uniqKey="Daoud A" first="Azhar S." last="Daoud">Azhar S. Daoud</name><affiliation><nlm:aff id="aff19"></nlm:aff></affiliation></author><author><name sortKey="Kivity, Sara" sort="Kivity, Sara" uniqKey="Kivity S" first="Sara" last="Kivity">Sara Kivity</name><affiliation><nlm:aff id="aff20"></nlm:aff></affiliation></author><author><name sortKey="Neufeld, Miriam Y" sort="Neufeld, Miriam Y" uniqKey="Neufeld M" first="Miriam Y." last="Neufeld">Miriam Y. Neufeld</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Mazarib, Aziz" sort="Mazarib, Aziz" uniqKey="Mazarib A" first="Aziz" last="Mazarib">Aziz Mazarib</name><affiliation><nlm:aff id="aff22"></nlm:aff></affiliation></author><author><name sortKey="Straussberg, Rachel" sort="Straussberg, Rachel" uniqKey="Straussberg R" first="Rachel" last="Straussberg">Rachel Straussberg</name><affiliation><nlm:aff id="aff21"></nlm:aff></affiliation></author><author><name sortKey="Walid, Simri" sort="Walid, Simri" uniqKey="Walid S" first="Simri" last="Walid">Simri Walid</name><affiliation><nlm:aff id="aff23"></nlm:aff></affiliation></author><author><name sortKey="Korczyn, Amos D" sort="Korczyn, Amos D" uniqKey="Korczyn A" first="Amos D." last="Korczyn">Amos D. Korczyn</name><affiliation><nlm:aff id="aff24"></nlm:aff></affiliation></author><author><name sortKey="Slusarski, Diane C" sort="Slusarski, Diane C" uniqKey="Slusarski D" first="Diane C." last="Slusarski">Diane C. Slusarski</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Berkovic, Samuel F" sort="Berkovic, Samuel F" uniqKey="Berkovic S" first="Samuel F." last="Berkovic">Samuel F. Berkovic</name><affiliation><nlm:aff id="aff25"></nlm:aff></affiliation></author><author><name sortKey="El Shanti, Hatem I" sort="El Shanti, Hatem I" uniqKey="El Shanti H" first="Hatem I." last="El-Shanti">Hatem I. El-Shanti</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation><nlm:aff id="aff26"></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="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia, where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in <italic>PRICKLE1</italic> (also known as <italic>RILP</italic> for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified <italic>PRICKLE1</italic> mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy.</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-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>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18976727</article-id><article-id pub-id-type="pmc">2668041</article-id><article-id pub-id-type="publisher-id">AJHG268</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2008.10.003</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>A Homozygous Mutation in Human <italic>PRICKLE1</italic> Causes an Autosomal-Recessive Progressive Myoclonus Epilepsy-Ataxia Syndrome</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Bassuk</surname><given-names>Alexander G.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Wallace</surname><given-names>Robyn H.</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Buhr</surname><given-names>Aimee</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Buller</surname><given-names>Andrew R.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Afawi</surname><given-names>Zaid</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Shimojo</surname><given-names>Masahito</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Miyata</surname><given-names>Shingo</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Shan</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Gonzalez-Alegre</surname><given-names>Pedro</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Griesbach</surname><given-names>Hilary L.</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Wu</surname><given-names>Shu</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Nashelsky</surname><given-names>Marcus</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Vladar</surname><given-names>Eszter K.</given-names></name><xref rid="aff11" ref-type="aff">11</xref><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>Antic</surname><given-names>Dragana</given-names></name><xref rid="aff11" ref-type="aff">11</xref><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>Ferguson</surname><given-names>Polly J.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Cirak</surname><given-names>Sebahattin</given-names></name><xref rid="aff16" ref-type="aff">16</xref></contrib><contrib contrib-type="author"><name><surname>Voit</surname><given-names>Thomas</given-names></name><xref rid="aff17" ref-type="aff">17</xref></contrib><contrib contrib-type="author"><name><surname>Scott</surname><given-names>Matthew P.</given-names></name><xref rid="aff12" ref-type="aff">12</xref><xref rid="aff13" ref-type="aff">13</xref><xref rid="aff14" ref-type="aff">14</xref><xref rid="aff15" ref-type="aff">15</xref></contrib><contrib contrib-type="author"><name><surname>Axelrod</surname><given-names>Jeffrey D.</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Gurnett</surname><given-names>Christina</given-names></name><xref rid="aff18" ref-type="aff">18</xref></contrib><contrib contrib-type="author"><name><surname>Daoud</surname><given-names>Azhar S.</given-names></name><xref rid="aff19" ref-type="aff">19</xref></contrib><contrib contrib-type="author"><name><surname>Kivity</surname><given-names>Sara</given-names></name><xref rid="aff20" ref-type="aff">20</xref></contrib><contrib contrib-type="author"><name><surname>Neufeld</surname><given-names>Miriam Y.</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Mazarib</surname><given-names>Aziz</given-names></name><xref rid="aff22" ref-type="aff">22</xref></contrib><contrib contrib-type="author"><name><surname>Straussberg</surname><given-names>Rachel</given-names></name><xref rid="aff21" ref-type="aff">21</xref></contrib><contrib contrib-type="author"><name><surname>Walid</surname><given-names>Simri</given-names></name><xref rid="aff23" ref-type="aff">23</xref></contrib><contrib contrib-type="author"><name><surname>Korczyn</surname><given-names>Amos D.</given-names></name><xref rid="aff24" ref-type="aff">24</xref></contrib><contrib contrib-type="author"><name><surname>Slusarski</surname><given-names>Diane C.</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Berkovic</surname><given-names>Samuel F.</given-names></name><email>s.berkovic@unimelb.edu.au</email><xref rid="aff25" ref-type="aff">25</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>El-Shanti</surname><given-names>Hatem I.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff26" ref-type="aff">26</xref></contrib></contrib-group><aff id="aff1"><addr-line><sup>1</sup>Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA</addr-line></aff><aff id="aff2"><addr-line><sup>2</sup>Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA</addr-line></aff><aff id="aff3"><addr-line><sup>3</sup>Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA</addr-line></aff><aff id="aff4"><addr-line><sup>4</sup>Department of Neurology, University of Iowa, Iowa City, IA 52242, USA</addr-line></aff><aff id="aff5"><addr-line><sup>5</sup>Department of Biology, University of Iowa, Iowa City, IA 52242, USA</addr-line></aff><aff id="aff6"><addr-line><sup>6</sup>Department of Pathology, University of Iowa, Iowa City, IA 52242, USA</addr-line></aff><aff id="aff7"><addr-line><sup>7</sup>Queensland Brain Institute, The University of Queensland, Brisbane 4072, Australia</addr-line></aff><aff id="aff8"><addr-line><sup>8</sup>Department of Neurology, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 64239, Israel</addr-line></aff><aff id="aff9"><addr-line><sup>9</sup>Department of Molecular and Cellular Biochemistry, University of Kentucky, Louisville, KY 40536, USA</addr-line></aff><aff id="aff10"><addr-line><sup>10</sup>Department of Anatomy & Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan</addr-line></aff><aff id="aff11"><addr-line><sup>11</sup>Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA</addr-line></aff><aff id="aff12"><addr-line><sup>12</sup>Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA</addr-line></aff><aff id="aff13"><addr-line><sup>13</sup>Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA</addr-line></aff><aff id="aff14"><addr-line><sup>14</sup>Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA</addr-line></aff><aff id="aff15"><addr-line><sup>15</sup>Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA</addr-line></aff><aff id="aff16"><addr-line><sup>16</sup>Universitätskinderklinik Essen, Abteilung für Allgemeine Pädiatrie mit Schwerpunkt Neuropädiatrie, 45122 Essen, Germany</addr-line></aff><aff id="aff17"><addr-line><sup>17</sup>Institut de Myologie Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France</addr-line></aff><aff id="aff18"><addr-line><sup>18</sup>Department of Neurology, Division Pediatric Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA</addr-line></aff><aff id="aff19"><addr-line><sup>19</sup>Department of Pediatrics, Jordan University of Science and Technology, Irbid 22110, Jordan</addr-line></aff><aff id="aff20"><addr-line><sup>20</sup>Epilepsy Unit, Schneider Children's Medical Center of Israel, Petach Tikvah 49202, Israel</addr-line></aff><aff id="aff21"><addr-line><sup>21</sup>Department of Child Neurology, Schneider Children's Medical Center of Israel, Petach Tikvah 49202, Israel</addr-line></aff><aff id="aff22"><addr-line><sup>22</sup>Kupat Holim Clalit, Nazareth 16000, Israel</addr-line></aff><aff id="aff23"><addr-line><sup>23</sup>Department of Neurology, Western Galilee Hospital, Nahariya 22100, Israel</addr-line></aff><aff id="aff24"><addr-line><sup>24</sup>Sieratzki Chair of Neurology, Tel Aviv University, Ramat Aviv 69978, Israel</addr-line></aff><aff id="aff25"><addr-line><sup>25</sup>Epilepsy Research Centre and Department of Medicine, University of Melbourne (Austin Health), Heidelberg West, Victoria 3161, Australia</addr-line></aff><aff id="aff26"><addr-line><sup>26</sup>Shafallah Medical Genetics Center, Doha, Qatar</addr-line></aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>s.berkovic@unimelb.edu.au</email></corresp></author-notes><pub-date pub-type="ppub"><day>17</day><month>11</month><year>2008</year></pub-date><volume>83</volume><issue>5</issue><fpage>572</fpage><lpage>581</lpage><history><date date-type="received"><day>19</day><month>8</month><year>2008</year></date><date date-type="rev-recd"><day>28</day><month>9</month><year>2008</year></date><date date-type="accepted"><day>3</day><month>10</month><year>2008</year></date></history><permissions><copyright-statement>© 2008 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved..</copyright-statement><copyright-year>2008</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder><license><p>This document may be redistributed and reused, subject to <ext-link ext-link-type="uri" xlink:href="http://www.elsevier.com/wps/find/authorsview.authors/supplementalterms1.0">certain conditions</ext-link>.</p></license></permissions><abstract><p>Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia, where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in <italic>PRICKLE1</italic> (also known as <italic>RILP</italic> for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified <italic>PRICKLE1</italic> mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy.</p></abstract></article-meta></front><floats-wrap><fig id="fig1"><label>Figure 1</label><caption><p>Pedigrees of the Affected Families, Representative Sequences, and Evolutionary Comparison of the Altered PRICKLE1 Amino Acid</p><p>Nine nuclear families from three pedigrees including 23 subjects with progressive myoclonus epilepsy and ataxia (pink symbol). Boxes on pedigrees indicate individuals previously reported by Berkovic et al.<xref rid="bib1" ref-type="bibr"><sup>1</sup></xref> (A), El-Shanti et al.<xref rid="bib2" ref-type="bibr"><sup>2</sup></xref> (B), and Straussberg et al.<xref rid="bib3" ref-type="bibr"><sup>3</sup></xref> (C). Dotted lines indicate individuals believed to be related, but the exact relationship was unknown. Subjects who probably had the familial syndrome but were not personally examined are shown in orange. Shared chromosome 12 haplotypes of affected subjects are shown on the top right. Haplotypes were remarkably stable within nuclear families and extended pedigrees. Individuals with epilepsy or ataxia, clinically distinct from the familial syndrome (green and purple symbols), did not share the haplotypes or have the <italic>PRICKLE1</italic> mutation. Representative DNA sequence chromograms from normal, carrier, and affected (mutant) individuals are in the bottom left panel with the red asterisks denoting the position of the abnormal nucleotide. Amino acid sequence alignment surrounding the altered amino acid for PRICKLE proteins in multiple species. pk1, Prickle1 protein; pk2, Prickle2 protein; esn, espinas protein; zfish, zebrafish. Accession numbers for the protein sequences are: human-pk1, NP_694571; human-pk2, NP_942559; mouse-pk1, NP_001028389; mouse-pk2, NP_001074615; platypus-pk1, XP_001505284; platypus-pk2, XP_001508261; chicken-pk1, XP_416036; chicken-pk2, XP_001234704; frog-pk1, NP_001016939; frog-pk-2, NP_001103517; zfish-pk1, NP_899185; zfish-pk2, NP_899186; fruit fly-pk1, NP_724534; fruit fly-esn, CAB64381; worm-pk1, NP_741435. The amino acid altered in the families and the corresponding amino acid in Prickle proteins from other species are boxed in red.</p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Expression of Prickle1 in Postnatal Mouse Brain</p><p>Prickle1 expression in cortex (A–D), hippocampus (E–H), cerebellum (I, J), and thalamus (K, L). For (A), (B), (E), (F), (I), and (J), Prickle1 antibody, raised against epitope corresponding to amino acids 339–514 of Prickle1, is labeled with green secondary, nuclear staining is in red. For (C), (D), (G), (H), (K), and (L), Prickle1 antibody, raised against epitope corresponding to amino acids 808–822 of Prickle1, is labeled in green. In (C), (D), (G), (H), (K), and (L), nuclear staining is in blue. In (C), (G), and (K), GFAP staining is in red. In (D), (H), and (L), NeuN, staining is in red. Arrows point to representative cerebellar Purkinje cells. 3v, third ventricle from coronal section; CA1, CA2, CA3, hippocampal <italic>Cornu Ammonis</italic> subregions; cb, cerebellum; cx, cerebral cortex; DG, dentate gyrus; hpc, hippocampus; th, thalamus. Magnification is 10× in (A), (E), and (I); 20× in (B), (F), (J), (K), and (L); 60× in (C), (D), (G), and (H). (A), (B), (E), (F), (I), and (J) are from P7 brain, (C), (D), (G), (H), (K), and (L) are from adult brain. (A)–(J) are from sagittal sections, (K) and (L) are coronal sections. A representative sample of sagittal sections from a P19 brain at multiple magnifications can be found in <xref rid="app2" ref-type="sec">Figure S1</xref>.</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Expression of PRICKLE1 in Adult Human Brain</p><p>Low-power (A–D) and high-power (E–H) confocal images from immunostaining of adult human thalamus (A, E), hippocampus (B, F), cerebral cortex (C, G), and cerebellum (D, H). PRICKLE1 staining is in green, NeuN is in red, and nuclear staining is in blue. Scale markers are represented on the bottom right corner of each image.</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>R104Q Mutant PRICKLE1 Has Impaired NRSF/REST Binding</p><p>Coimmunoprecipitation of REST with wild-type (WT) or R104Q mutant (MUT) encoding PRICKLE1 demonstrates decreased REST binding for MUT PRICKLE1. MYC-REST and either GFP-tagged WT or R104Q MUT PRICKLE1 plasmids were transfected into HeLa cells. Cell lysates were prepared in RIPA buffer and immunoprecipitated with agarose-conjugated anti-GFP antibody (A) or anti-MYC antibody (B). Immunoprecipitates (IP) were subjected to SDS-PAGE followed by western blotting (WB) with MYC or GFP antibodies. WB antibody noted to left of gels. The input (1/5) of immunoprecipitation is shown in the “Lys” lanes. Arrows to the right of the gels note the position of MYC-REST and GFP-PRICKLE1.</p></caption><graphic xlink:href="gr4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Subcellular Localization of Recombinant MYC-REST and WT or MUT PRICKLE1</p><p>(A) HeLa cells were transfected with MYC-REST and WT PRICKLE1 or MUT PRICKLE1, as noted on the top of the images in (A). Antibody staining with ANTI-MYC antibody (red), ANTI-PRICKLE1 antibody (green), DAPI nuclear staining (blue), and MERGED confocal images are noted on the left. Scale bar represents 9 microns. All confocal images were captured with identical exposure settings. The white arrow in the merged WT-PRICKLE1+MYC-REST marks a cell with relatively less WT PRICKLE1 expressed versus the two other WT PRICKLE1-expressing cells in the same panel. Note that increased REST in the nucleus is inversely proportional to WT PRICKLE1 expression, whereas the nuclear REST signal is strong even in the presence of a strong MUT PRICKLE1 signal (bottom right).</p><p>(B) Quantification of nuclear REST in PRICKLE1 versus mutant PRICKLE1 cotransfections. Results are the mean (±SD) of 100 cells for each group.</p></caption><graphic xlink:href="gr5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>Mutant prickle1 Shows Decreased Activity In Vivo in Zebrafish</p><p>(A–D) Equivalent amounts of RNA encoding wild-type zebrafish <italic>prickle1</italic> (<italic>pk</italic>-wt) or zebrafish <italic>prickle1</italic> encoding the human R104Q homologous amino acid (<italic>pk</italic>-mut) were injected into zebrafish embryos and assayed for convergence extension defects by morphology (A) wild-type compared to (B) pk-overexpression, anterior to the left and with molecular markers to axial tissues in (C) wild-type and (D) pk-overexpressing embryos, anterior to the top.</p><p>(E) Decreased gastrulation defects are observed in mutant <italic>prickle1</italic> expressing embryos compared to wild-type <italic>prickle</italic> expressing embryos. The mutant Prickle1 showed significantly decreased overexpression phenotype, with a p value of 0.01 by the Fisher's exact test.</p></caption><graphic xlink:href="gr6"></graphic></fig><table-wrap position="float" id="tbl1"><label>Table 1</label><caption><p>Comparison of the Progressive Myoclonus Epilepsy-Ataxia Syndrome Described Here to Classical Unverricht-Lundborg Disease</p></caption><table frame="hsides" rules="groups"><thead><tr><th></th><th><bold>Progresssive Myoclonus Epilepsy-Ataxia Syndrome</bold></th><th><bold>Unverricht-Lundborg Disease</bold><xref rid="tblfn1" ref-type="table-fn">a</xref></th></tr></thead><tbody><tr><td>First symptom</td><td>ataxia around age 4 yr</td><td>myoclonic or tonic-clonic seizures</td></tr><tr><td>Seizure onset: mean</td><td>7 yr</td><td>10–11 yr</td></tr><tr><td>Seizure onset: range</td><td>5–10 yr</td><td>6–16 yr</td></tr><tr><td>Progressive features</td><td>worsening myoclonus, ataxia, impaired up-gaze</td><td>worsening myoclonus, ataxia</td></tr><tr><td>Cognitive decline</td><td>mild or absent</td><td>mild or absent</td></tr><tr><td>Mode of inheritance</td><td>autosomal recessive</td><td>autosomal recessive</td></tr><tr><td>Linkage</td><td>12p11–q13</td><td>21q22.3</td></tr><tr><td>Gene</td><td><italic>PRICKLE1</italic></td><td><italic>Cystatin B</italic></td></tr></tbody></table><table-wrap-foot><fn id="tblfn1"><label>a</label><p>Modified and updated from Berkovic et al.<xref rid="bib1" ref-type="bibr"><sup>1</sup></xref></p></fn></table-wrap-foot></table-wrap></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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