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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mutations in the Small GTPase Gene <italic>RAB39B</italic> Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly</title><author><name sortKey="Giannandrea, Maila" sort="Giannandrea, Maila" uniqKey="Giannandrea M" first="Maila" last="Giannandrea">Maila Giannandrea</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Bianchi, Veronica" sort="Bianchi, Veronica" uniqKey="Bianchi V" first="Veronica" last="Bianchi">Veronica Bianchi</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Mignogna, Maria Lidia" sort="Mignogna, Maria Lidia" uniqKey="Mignogna M" first="Maria Lidia" last="Mignogna">Maria Lidia Mignogna</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Sirri, Alessandra" sort="Sirri, Alessandra" uniqKey="Sirri A" first="Alessandra" last="Sirri">Alessandra Sirri</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Carrabino, Salvatore" sort="Carrabino, Salvatore" uniqKey="Carrabino S" first="Salvatore" last="Carrabino">Salvatore Carrabino</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="D Elia, Errico" sort="D Elia, Errico" uniqKey="D Elia E" first="Errico" last="D'Elia">Errico D'Elia</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Vecellio, Matteo" sort="Vecellio, Matteo" uniqKey="Vecellio M" first="Matteo" last="Vecellio">Matteo Vecellio</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Russo, Silvia" sort="Russo, Silvia" uniqKey="Russo S" first="Silvia" last="Russo">Silvia Russo</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Cogliati, Francesca" sort="Cogliati, Francesca" uniqKey="Cogliati F" first="Francesca" last="Cogliati">Francesca Cogliati</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Larizza, Lidia" sort="Larizza, Lidia" uniqKey="Larizza L" first="Lidia" last="Larizza">Lidia Larizza</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Ropers, Hans Hilger" sort="Ropers, Hans Hilger" uniqKey="Ropers H" first="Hans-Hilger" last="Ropers">Hans-Hilger Ropers</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Tzschach, Andreas" sort="Tzschach, Andreas" uniqKey="Tzschach A" first="Andreas" last="Tzschach">Andreas Tzschach</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Kalscheuer, Vera" sort="Kalscheuer, Vera" uniqKey="Kalscheuer V" first="Vera" last="Kalscheuer">Vera Kalscheuer</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Oehl Jaschkowitz, Barbara" sort="Oehl Jaschkowitz, Barbara" uniqKey="Oehl Jaschkowitz B" first="Barbara" last="Oehl-Jaschkowitz">Barbara Oehl-Jaschkowitz</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Skinner, Cindy" sort="Skinner, Cindy" uniqKey="Skinner C" first="Cindy" last="Skinner">Cindy Skinner</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Schwartz, Charles E" sort="Schwartz, Charles E" uniqKey="Schwartz C" first="Charles E." last="Schwartz">Charles E. Schwartz</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author><author><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name><affiliation><nlm:aff id="aff10"></nlm:aff></affiliation></author><author><name sortKey="Raynaud, Martine" sort="Raynaud, Martine" uniqKey="Raynaud M" first="Martine" last="Raynaud">Martine Raynaud</name><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation></author><author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name><affiliation><nlm:aff id="aff12"></nlm:aff></affiliation></author><author><name sortKey="De Brouwer, Arjan P M" sort="De Brouwer, Arjan P M" uniqKey="De Brouwer A" first="Arjan P. M." last="De Brouwer">Arjan P. M. De Brouwer</name><affiliation><nlm:aff id="aff13"></nlm:aff></affiliation></author><author><name sortKey="Toniolo, Daniela" sort="Toniolo, Daniela" uniqKey="Toniolo D" first="Daniela" last="Toniolo">Daniela Toniolo</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation><nlm:aff id="aff14"></nlm:aff></affiliation></author><author><name sortKey="D Adamo, Patrizia" sort="D Adamo, Patrizia" uniqKey="D Adamo P" first="Patrizia" last="D'Adamo">Patrizia D'Adamo</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20159109</idno><idno type="pmc">2820185</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820185</idno><idno type="RBID">PMC:2820185</idno><idno type="doi">10.1016/j.ajhg.2010.01.011</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">001706</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001706</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutations in the Small GTPase Gene <italic>RAB39B</italic> Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly</title><author><name sortKey="Giannandrea, Maila" sort="Giannandrea, Maila" uniqKey="Giannandrea M" first="Maila" last="Giannandrea">Maila Giannandrea</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Bianchi, Veronica" sort="Bianchi, Veronica" uniqKey="Bianchi V" first="Veronica" last="Bianchi">Veronica Bianchi</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Mignogna, Maria Lidia" sort="Mignogna, Maria Lidia" uniqKey="Mignogna M" first="Maria Lidia" last="Mignogna">Maria Lidia Mignogna</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Sirri, Alessandra" sort="Sirri, Alessandra" uniqKey="Sirri A" first="Alessandra" last="Sirri">Alessandra Sirri</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Carrabino, Salvatore" sort="Carrabino, Salvatore" uniqKey="Carrabino S" first="Salvatore" last="Carrabino">Salvatore Carrabino</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="D Elia, Errico" sort="D Elia, Errico" uniqKey="D Elia E" first="Errico" last="D'Elia">Errico D'Elia</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Vecellio, Matteo" sort="Vecellio, Matteo" uniqKey="Vecellio M" first="Matteo" last="Vecellio">Matteo Vecellio</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Russo, Silvia" sort="Russo, Silvia" uniqKey="Russo S" first="Silvia" last="Russo">Silvia Russo</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Cogliati, Francesca" sort="Cogliati, Francesca" uniqKey="Cogliati F" first="Francesca" last="Cogliati">Francesca Cogliati</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Larizza, Lidia" sort="Larizza, Lidia" uniqKey="Larizza L" first="Lidia" last="Larizza">Lidia Larizza</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Ropers, Hans Hilger" sort="Ropers, Hans Hilger" uniqKey="Ropers H" first="Hans-Hilger" last="Ropers">Hans-Hilger Ropers</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Tzschach, Andreas" sort="Tzschach, Andreas" uniqKey="Tzschach A" first="Andreas" last="Tzschach">Andreas Tzschach</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Kalscheuer, Vera" sort="Kalscheuer, Vera" uniqKey="Kalscheuer V" first="Vera" last="Kalscheuer">Vera Kalscheuer</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Oehl Jaschkowitz, Barbara" sort="Oehl Jaschkowitz, Barbara" uniqKey="Oehl Jaschkowitz B" first="Barbara" last="Oehl-Jaschkowitz">Barbara Oehl-Jaschkowitz</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Skinner, Cindy" sort="Skinner, Cindy" uniqKey="Skinner C" first="Cindy" last="Skinner">Cindy Skinner</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Schwartz, Charles E" sort="Schwartz, Charles E" uniqKey="Schwartz C" first="Charles E." last="Schwartz">Charles E. Schwartz</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author><author><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name><affiliation><nlm:aff id="aff10"></nlm:aff></affiliation></author><author><name sortKey="Raynaud, Martine" sort="Raynaud, Martine" uniqKey="Raynaud M" first="Martine" last="Raynaud">Martine Raynaud</name><affiliation><nlm:aff id="aff11"></nlm:aff></affiliation></author><author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name><affiliation><nlm:aff id="aff12"></nlm:aff></affiliation></author><author><name sortKey="De Brouwer, Arjan P M" sort="De Brouwer, Arjan P M" uniqKey="De Brouwer A" first="Arjan P. M." last="De Brouwer">Arjan P. M. De Brouwer</name><affiliation><nlm:aff id="aff13"></nlm:aff></affiliation></author><author><name sortKey="Toniolo, Daniela" sort="Toniolo, Daniela" uniqKey="Toniolo D" first="Daniela" last="Toniolo">Daniela Toniolo</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation><nlm:aff id="aff14"></nlm:aff></affiliation></author><author><name sortKey="D Adamo, Patrizia" sort="D Adamo, Patrizia" uniqKey="D Adamo P" first="Patrizia" last="D'Adamo">Patrizia D'Adamo</name><affiliation><nlm:aff id="aff1"></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="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Human Mental Retardation (MR) is a common and highly heterogeneous pediatric disorder affecting around 3% of the general population; at least 215 X-linked MR (XLMR) conditions have been described, and mutations have been identified in 83 different genes, encoding proteins with a variety of function, such as chromatin remodeling, synaptic function, and intracellular trafficking. The small GTPases of the RAB family, which play an essential role in intracellular vesicular trafficking, have been shown to be involved in MR. We report here the identification of mutations in the small GTPase <italic>RAB39B</italic> gene in two male patients. One mutation in family X (D-23) introduced a stop codon seven amino acids after the start codon (c.21C > A; p.Y7X). A second mutation, in the MRX72 family, altered the 5′ splice site (c.215+1G > A) and normal splicing. Neither instance produced a protein. Mutations segregate with the disease in the families, and in some family members intellectual disabilities were associated with autism spectrum disorder, epileptic seizures, and macrocephaly. We show that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that is localized to the Golgi compartment. Its downregulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance. Our results demonstrate developmental and functional neuronal alteration as a consequence of downregulation of RAB39B and emphasize the critical role of vesicular trafficking in the development of neurons and human intellectual abilities.</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">20159109</article-id><article-id pub-id-type="pmc">2820185</article-id><article-id pub-id-type="publisher-id">AJHG558</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2010.01.011</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Mutations in the Small GTPase Gene <italic>RAB39B</italic> Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Giannandrea</surname><given-names>Maila</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Bianchi</surname><given-names>Veronica</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Mignogna</surname><given-names>Maria Lidia</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Sirri</surname><given-names>Alessandra</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Carrabino</surname><given-names>Salvatore</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>D'Elia</surname><given-names>Errico</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">15</xref></contrib><contrib contrib-type="author"><name><surname>Vecellio</surname><given-names>Matteo</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn2" ref-type="fn">16</xref></contrib><contrib contrib-type="author"><name><surname>Russo</surname><given-names>Silvia</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Cogliati</surname><given-names>Francesca</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Larizza</surname><given-names>Lidia</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Ropers</surname><given-names>Hans-Hilger</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Tzschach</surname><given-names>Andreas</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Kalscheuer</surname><given-names>Vera</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Oehl-Jaschkowitz</surname><given-names>Barbara</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Skinner</surname><given-names>Cindy</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Schwartz</surname><given-names>Charles E.</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Gecz</surname><given-names>Jozef</given-names></name><xref rid="aff8" ref-type="aff">8</xref><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Van Esch</surname><given-names>Hilde</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Raynaud</surname><given-names>Martine</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Chelly</surname><given-names>Jamel</given-names></name><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>de Brouwer</surname><given-names>Arjan P.M.</given-names></name><xref rid="aff13" ref-type="aff">13</xref></contrib><contrib contrib-type="author"><name><surname>Toniolo</surname><given-names>Daniela</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff14" ref-type="aff">14</xref></contrib><contrib contrib-type="author"><name><surname>D'Adamo</surname><given-names>Patrizia</given-names></name><email>p.dadamo@hsr.it</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><addr-line><sup>1</sup>Dulbecco Telethon Institute at Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy</addr-line></aff><aff id="aff2"><addr-line><sup>2</sup>Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy</addr-line></aff><aff id="aff3"><addr-line><sup>3</sup>Molecular Genetics Laboratory, Istituto Auxologico Italiano, 20145 Milan, Italy</addr-line></aff><aff id="aff4"><addr-line><sup>4</sup>Chirurgia e Odontoiatria Università di Milano Polo Osp. San Paolo, 20142 Milan, Italy</addr-line></aff><aff id="aff5"><addr-line><sup>5</sup>Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</addr-line></aff><aff id="aff6"><addr-line><sup>6</sup>Practice of Human Genetics, 66424 Homburg (Saar), Germany</addr-line></aff><aff id="aff7"><addr-line><sup>7</sup>J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA</addr-line></aff><aff id="aff8"><addr-line><sup>8</sup>SA Pathology, Women's and Children's Hospital, North Adelaide, SA 5006, Australia</addr-line></aff><aff id="aff9"><addr-line><sup>9</sup>Department of Paediatrics, University of Adelaide, 5006 Adelaide, Australia</addr-line></aff><aff id="aff10"><addr-line><sup>10</sup>Center for Human Genetics, University Hospital Leuven, 3000 Leuven, Belgium</addr-line></aff><aff id="aff11"><addr-line><sup>11</sup>Centre Hospitalier Régional Universitaire de Tours, Service de Génétique and INSERM, U930, 37044 Tours, France</addr-line></aff><aff id="aff12"><addr-line><sup>12</sup>Université Paris Descartes; Institut Cochin; INSERM, U567; and Centre National de la Recherche Scientifique, UMR 8104, 75014 Paris, France</addr-line></aff><aff id="aff13"><addr-line><sup>13</sup>Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, 6500 Nijmegen, The Netherlands</addr-line></aff><aff id="aff14"><addr-line><sup>14</sup>Institute of Molecular Genetics-CNR, 20182 Pavia, Italy</addr-line></aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>p.dadamo@hsr.it</email></corresp><fn id="fn1"><label>15</label><p>Present address: Department of Experimental Oncology, European Institute of Oncology, 20139 Milan, Italy</p></fn><fn id="fn2"><label>16</label><p>Present address: Vascular Biology and Gene Therapy Laboratory, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy</p></fn></author-notes><pub-date pub-type="ppub"><day>12</day><month>2</month><year>2010</year></pub-date><volume>86</volume><issue>2</issue><fpage>185</fpage><lpage>195</lpage><history><date date-type="received"><day>25</day><month>10</month><year>2009</year></date><date date-type="rev-recd"><day>28</day><month>12</month><year>2009</year></date><date date-type="accepted"><day>11</day><month>1</month><year>2010</year></date></history><permissions><copyright-statement>© 2010 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved..</copyright-statement><copyright-year>2010</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>Human Mental Retardation (MR) is a common and highly heterogeneous pediatric disorder affecting around 3% of the general population; at least 215 X-linked MR (XLMR) conditions have been described, and mutations have been identified in 83 different genes, encoding proteins with a variety of function, such as chromatin remodeling, synaptic function, and intracellular trafficking. The small GTPases of the RAB family, which play an essential role in intracellular vesicular trafficking, have been shown to be involved in MR. We report here the identification of mutations in the small GTPase <italic>RAB39B</italic> gene in two male patients. One mutation in family X (D-23) introduced a stop codon seven amino acids after the start codon (c.21C > A; p.Y7X). A second mutation, in the MRX72 family, altered the 5′ splice site (c.215+1G > A) and normal splicing. Neither instance produced a protein. Mutations segregate with the disease in the families, and in some family members intellectual disabilities were associated with autism spectrum disorder, epileptic seizures, and macrocephaly. We show that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that is localized to the Golgi compartment. Its downregulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance. Our results demonstrate developmental and functional neuronal alteration as a consequence of downregulation of RAB39B and emphasize the critical role of vesicular trafficking in the development of neurons and human intellectual abilities.</p></abstract></article-meta></front><floats-wrap><fig id="fig1"><label>Figure 1</label><caption><p><italic>RAB39B</italic> Mutations in Family X (D-23) and MRX72</p><p>(A and B) The upper panels show the corresponding sequence from a normal individual; the lower panels are from the patients. Arrows indicate the mutations. Sequence numbers refer to the human <italic>RAB39B</italic> cDNA (NM_171998).</p><p>(C) Immunoblot analysis performed on 30 μg of total protein extracted from HeLa cells transfected with pFLAG-RAB39B constructs containing the wild-type <italic>RAB39B</italic> cDNA (WT), family X (D-23) mutated cDNA, or MRX72 cDNA. The 24-kDa band corresponds to FLAG-RAB39B fusion protein, and the 51-kDa band corresponds to beta-tubulin. MOCK: cells transfected with pCMV2-FLAG. NT: cells not transfected.</p><p>(D) Pedigree of family X (D-23).</p><p>(E) Pedigree of MRX72. Black squares indicate males with mental retardation, dotted circles indicate carrier females, and open symbols indicate unaffected individuals. Asterisks indicate family members who have been sequenced in this study.</p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Expression Analysis on Different Human and Mouse Tissues</p><p>(A) Expression of <italic>RAB39B</italic> transcript in different human tissues.</p><p>(B) Expression of <italic>Rab39b</italic> transcript in mouse tissues.</p><p>(C) Expression profile of <italic>Rab39b</italic> and <italic>Rab39a</italic> in mouse total brain during post-natal (P) development (from P1 to P180; for each age point, n = 8). Data were expressed as <italic>Rab39b</italic> or <italic>Rab39a</italic> expression normalized to <italic>Histone-H3</italic> (2<sup>-ΔCt(<italic>Rab39b</italic>–H3)</sup>) (±SE).</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p><italic>Rab39b</italic> Is Specifically Expressed in Neurons</p><p>(A) In situ hybridization analysis of <italic>Rab39b</italic> on P90 mouse brain. Light-microscopic images showing the distribution of <italic>Rab39b</italic> mRNA in 20 μm mouse brain sagittal sections. Anti-sense (A) and sense (B) <italic>Rab39b</italic> probe.</p><p>(C–F) Enlargements of specific regions: CC, cerebral cortex; CbC, cerebellar cortex; Hi, hippocampus; OB, olfactory bulb; T, thalamus; S, subiculum; CA1 and CA3, fields of the hippocampus; DG, dentate gyrus; PL, Purkinje layer; and Mi, mitral cells. Scale bars represent 2 mm (A and B) and 0.1 mm (C–F).</p><p>(G) <italic>Rab39b</italic> expression normalized to <italic>Histone-H3</italic> (2<sup>-ΔCt(<italic>Rab39b</italic>–H3)</sup>) in neuronal cell types. P2 mouse cerebral cortices were dissected, dissociated in trypsin medium, and plated. Different neuronal cell types were prepared as described.<xref rid="bib14" ref-type="bibr"><sup>14</sup></xref><italic>Rab39b</italic> is specifically expressed in neuronal precursors and neurons.</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>RAB39B Intracellular Localization in Mouse Hippocampal Neurons</p><p>Neurons were transduced at 3 DIV with pCCL-RAB39B lentiviral particles (green) at an MOI of 1 and analyzed at 7 DIV. The major colocalization was with GM130 (<italic>cis</italic>-Golgi) and GIANTIN (Golgi complex), VAMP4 and SYNTAXIN16 (STX16)—involved in trafficking from the cell surface to the trans-Golgi network (TGN)—and SYNTAXIN13 (STX13) and RAB11, which are present in recycling endosomes. No colocalization was observed with the adaptor protein 2 (AP2). The scale bar represents 10 μm.</p></caption><graphic xlink:href="gr4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>RAB39B Is Involved in Neurite Differentiation</p><p>Hippocampal neurons were transduced with lentiviral particles containing shRab39b and shScramble at an MOI of 1. The downregulation of the endogenous <italic>Rab39b</italic> RNA level was quantified at 3 DIV by qRT-PCR, and 40% reduction was observed in shRab39b-transduced neurons.</p><p>(A) There was a significant difference (p = 0.005) in the mean number of growth cones (GCs) at each neurite terminal (±SE) in shRab39b neurons (3.1 ± 0.1) versus shScramble neurons (3.8 ± 0.1) (mean ± SEM).</p><p>(B) There was a significant difference (p = 0.05) in the mean area of GCs (±SE) in shRab39b neurons versus shScramble neurons (38.7 ± 2.8 [mean ± SEM] and 30.8 ± 2.4, respectively).</p><p>(C) TRITC-Phalloidin immunostaining revealed altered GC morphology (enlargement of GC morphology in right panel). The scale bar represents 10 μm.</p><p>(D) For Sholl analysis,<xref rid="bib12" ref-type="bibr"><sup>12</sup></xref> as a measure of neuronal differentiation, a mask of concentric circles 5 μm apart was created and superimposed on neuronal cells. The first 10 μm from the center of the mask corresponds to the neuronal cell body. Repeated-measures ANOVA revealed significant differences between treatments, where F (1,147) = 6.6, p = 0.01, and between treatment and Sholl category (μm from the cell body), where F (1,5) = 2.3, p = 0.04. Factorial ANOVA for each Sholl category revealed a significant p value for 30 μm [F (1,147) = 9.3, p = 0.003], 35 μm [F (1,147) = 7.6, p = 0.006], and 40 μm [F (1,147) = 7.2; p = 0.007].</p><p><sup>∗</sup>p < 0.05; <sup>∗∗</sup>p < 0.01; <sup>∗∗∗</sup>p < 0.001. Data are expressed as means ±SE.</p></caption><graphic xlink:href="gr5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>RAB39B Localizes to Golgi-Derived Vesicles</p><p>(A) Hippocampal neurons transduced immediately after being plated with pCCL-RAB39B lentiviral particles at an MOI of 1 and immunostained at 3 DIV. TRITC-Phalloidin and anti-Tuj1 immunostaining revealed that RAB39B occupied a region similar to that of the GC actin domain.</p><p>(B) A partial colocalization was observed with GIANTIN, as a marker for the Golgi-derived vesicles, as shown by the arrows in the enlargement in the merged right panel.</p><p>The scale bar represents 10 μm.</p></caption><graphic xlink:href="gr6"></graphic></fig><fig id="fig7"><label>Figure 7</label><caption><p>RAB39B Is Involved in Synapse Formation</p><p>Hippocampal neurons were transduced immediately after being plating with shRab39b and shScramble lentiviral particles at an MOI of 1. The downregulation of the endogenous <italic>Rab39b</italic> RNA level was quantified at 7 DIV by qRT-PCR, and 70% reduction was observed in shRab39b-transduced neurons. (A and B) SYNAPSIN1 immunostaining and quantification showed a 49% reduction in the SYN1 pre-synaptic compartment on shRab39b compared to shScramble neurons.</p><p>(C) FM4-64-positive labeling showed a 40% reduction for shRab39b neurons compared to shScramble.</p><p>The scale bar represents 10 μm. <sup>∗∗∗</sup>p < 0.001. Data are expressed as means ±SE.</p></caption><graphic xlink:href="gr7"></graphic></fig><table-wrap position="float" id="tbl1"><label>Table 1</label><caption><p>Clinical Evaluation of Family X (D-23)</p></caption><table frame="hsides" rules="groups"><thead><tr><th><bold>Clinical Feature</bold></th><th><bold>II-3</bold></th><th><bold>II-4</bold></th><th><bold>III-1</bold></th><th><bold>III-2</bold></th><th><bold>III-3</bold></th><th><bold>III-4</bold></th></tr></thead><tbody><tr><td>Age (yr)</td><td>52</td><td>50</td><td>19</td><td>16</td><td>13</td><td>13</td></tr><tr><td>Height (cm)</td><td>163 (<3<sup>rd</sup> percentile)</td><td>170 (3<sup>rd</sup> percentile)</td><td>178.5 (50<sup>th</sup> percentile)</td><td>177.5 (50<sup>th</sup> percentile)</td><td>145.5 (3<sup>rd</sup> percentile)</td><td>145.7 (3<sup>rd</sup> percentile)</td></tr><tr><td>OFC</td><td>59 (>97<sup>th</sup> percentile)</td><td>62.5 (>97<sup>th</sup> percentile)</td><td>60.5 (>97<sup>th</sup> percentile)</td><td>56.5 (>97<sup>th</sup> percentile)</td><td>57 (>97<sup>th</sup> percentile)</td><td>56.5 (>97<sup>th</sup> percentile)</td></tr><tr><td>Degree of MR</td><td>mild</td><td>severe</td><td>moderate</td><td>moderate</td><td>moderate</td><td>severe</td></tr><tr><td>Additional features</td><td>-</td><td>-</td><td>obesity</td><td>-</td><td>autism</td><td>autism</td></tr></tbody></table><table-wrap-foot><fn><p>In family X (D-23), four brothers and two maternal uncles were mentally retarded. The pedigree of the family is shown in <xref rid="fig1" ref-type="fig">Figure 1</xref>D. Patients III-3 and III-4 were twins. A sister of the two uncles (II-7) was mentally normal and died of a brain tumor at the age of 21 years. The degree of mental retardation ranged from mild (II-3) to severe (II-4 and III-4). All six patients had macrocephaly. Brain MRI scans in patients III-3 and III-4 and a CT scan in patient III-1 revealed no abnormalities. Height ranged from short stature in II-3, II-4, III-3, and III-4 to normal height in III-1 and III-2. Clinical examination of the patients revealed neither additional malformations nor significant facial dysmorphic features.</p></fn></table-wrap-foot></table-wrap></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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