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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Characterization of novel <italic>SLC6A8</italic> variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database</title><author><name sortKey="Betsalel, Ofir T" sort="Betsalel, Ofir T" uniqKey="Betsalel O" first="Ofir T" last="Betsalel">Ofir T. Betsalel</name><affiliation><nlm:aff id="aff1"><institution>Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Rosenberg, Efraim H" sort="Rosenberg, Efraim H" uniqKey="Rosenberg E" first="Efraim H" last="Rosenberg">Efraim H. Rosenberg</name><affiliation><nlm:aff id="aff1"><institution>Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Department of Pathology, The Netherlands Cancer Institute</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Almeida, Ligia S" sort="Almeida, Ligia S" uniqKey="Almeida L" first="Ligia S" last="Almeida">Ligia S. Almeida</name><affiliation><nlm:aff id="aff1"><institution>Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Medical Genetics Center, National Institute of Health, INSA</institution>, Porto,<country>Portugal</country></nlm:aff></affiliation></author><author><name sortKey="Kleefstra, Tjitske" sort="Kleefstra, Tjitske" uniqKey="Kleefstra T" first="Tjitske" last="Kleefstra">Tjitske Kleefstra</name><affiliation><nlm:aff id="aff4"><institution>Department of Human Genetics, Radboud University Nijmegen Medical Center</institution>, Nijmegen,<country>The Netherlands</country></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="aff5"><institution>Greenwood Genetics Center</institution>, Greenwood, SC,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Valayannopoulos, Vassili" sort="Valayannopoulos, Vassili" uniqKey="Valayannopoulos V" first="Vassili" last="Valayannopoulos">Vassili Valayannopoulos</name><affiliation><nlm:aff id="aff6"><institution>Department of Metabolic Disorders, Necker-Enfants Malades Hospital</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Abdul Rahman, Omar" sort="Abdul Rahman, Omar" uniqKey="Abdul Rahman O" first="Omar" last="Abdul-Rahman">Omar Abdul-Rahman</name><affiliation><nlm:aff id="aff7"><institution>Department of Pediatrics, University of Mississippi Medical Center</institution>, Jackson, MS,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Poplawski, Nicola" sort="Poplawski, Nicola" uniqKey="Poplawski N" first="Nicola" last="Poplawski">Nicola Poplawski</name><affiliation><nlm:aff id="aff8"><institution>South Australian Clinical Genetics Service, Women's and Children's Hospital</institution>, North Adelaide, South Australia,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Vilarinho, Laura" sort="Vilarinho, Laura" uniqKey="Vilarinho L" first="Laura" last="Vilarinho">Laura Vilarinho</name><affiliation><nlm:aff id="aff3"><institution>Medical Genetics Center, National Institute of Health, INSA</institution>, Porto,<country>Portugal</country></nlm:aff></affiliation></author><author><name sortKey="Wolf, Philipp" sort="Wolf, Philipp" uniqKey="Wolf P" first="Philipp" last="Wolf">Philipp Wolf</name><affiliation><nlm:aff id="aff9"><institution>Department of Neuropediatrics, DRK Children Clinic Siegen</institution>, Siegen,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Den Dunnen, Johan T" sort="Den Dunnen, Johan T" uniqKey="Den Dunnen J" first="Johan T" last="Den Dunnen">Johan T. Den Dunnen</name><affiliation><nlm:aff id="aff10"><institution>Department of Human and Clinical Genetics, Leiden University Medical Center</institution>, Leiden,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Jakobs, Cornelis" sort="Jakobs, Cornelis" uniqKey="Jakobs C" first="Cornelis" last="Jakobs">Cornelis Jakobs</name><affiliation><nlm:aff id="aff1"><institution>Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Salomons, Gajja S" sort="Salomons, Gajja S" uniqKey="Salomons G" first="Gajja S" last="Salomons">Gajja S. Salomons</name><affiliation><nlm:aff id="aff1"><institution>Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20717164</idno><idno type="pmc">3039501</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039501</idno><idno type="RBID">PMC:3039501</idno><idno type="doi">10.1038/ejhg.2010.134</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000056</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000056</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Characterization of novel <italic>SLC6A8</italic> variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database</title><author><name sortKey="Betsalel, Ofir T" sort="Betsalel, Ofir T" uniqKey="Betsalel O" first="Ofir T" last="Betsalel">Ofir T. Betsalel</name><affiliation><nlm:aff id="aff1"><institution>Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Rosenberg, Efraim H" sort="Rosenberg, Efraim H" uniqKey="Rosenberg E" first="Efraim H" last="Rosenberg">Efraim H. Rosenberg</name><affiliation><nlm:aff id="aff1"><institution>Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Department of Pathology, The Netherlands Cancer Institute</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Almeida, Ligia S" sort="Almeida, Ligia S" uniqKey="Almeida L" first="Ligia S" last="Almeida">Ligia S. Almeida</name><affiliation><nlm:aff id="aff1"><institution>Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Medical Genetics Center, National Institute of Health, INSA</institution>, Porto,<country>Portugal</country></nlm:aff></affiliation></author><author><name sortKey="Kleefstra, Tjitske" sort="Kleefstra, Tjitske" uniqKey="Kleefstra T" first="Tjitske" last="Kleefstra">Tjitske Kleefstra</name><affiliation><nlm:aff id="aff4"><institution>Department of Human Genetics, Radboud University Nijmegen Medical Center</institution>, Nijmegen,<country>The Netherlands</country></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="aff5"><institution>Greenwood Genetics Center</institution>, Greenwood, SC,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Valayannopoulos, Vassili" sort="Valayannopoulos, Vassili" uniqKey="Valayannopoulos V" first="Vassili" last="Valayannopoulos">Vassili Valayannopoulos</name><affiliation><nlm:aff id="aff6"><institution>Department of Metabolic Disorders, Necker-Enfants Malades Hospital</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Abdul Rahman, Omar" sort="Abdul Rahman, Omar" uniqKey="Abdul Rahman O" first="Omar" last="Abdul-Rahman">Omar Abdul-Rahman</name><affiliation><nlm:aff id="aff7"><institution>Department of Pediatrics, University of Mississippi Medical Center</institution>, Jackson, MS,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Poplawski, Nicola" sort="Poplawski, Nicola" uniqKey="Poplawski N" first="Nicola" last="Poplawski">Nicola Poplawski</name><affiliation><nlm:aff id="aff8"><institution>South Australian Clinical Genetics Service, Women's and Children's Hospital</institution>, North Adelaide, South Australia,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Vilarinho, Laura" sort="Vilarinho, Laura" uniqKey="Vilarinho L" first="Laura" last="Vilarinho">Laura Vilarinho</name><affiliation><nlm:aff id="aff3"><institution>Medical Genetics Center, National Institute of Health, INSA</institution>, Porto,<country>Portugal</country></nlm:aff></affiliation></author><author><name sortKey="Wolf, Philipp" sort="Wolf, Philipp" uniqKey="Wolf P" first="Philipp" last="Wolf">Philipp Wolf</name><affiliation><nlm:aff id="aff9"><institution>Department of Neuropediatrics, DRK Children Clinic Siegen</institution>, Siegen,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Den Dunnen, Johan T" sort="Den Dunnen, Johan T" uniqKey="Den Dunnen J" first="Johan T" last="Den Dunnen">Johan T. Den Dunnen</name><affiliation><nlm:aff id="aff10"><institution>Department of Human and Clinical Genetics, Leiden University Medical Center</institution>, Leiden,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Jakobs, Cornelis" sort="Jakobs, Cornelis" uniqKey="Jakobs C" first="Cornelis" last="Jakobs">Cornelis Jakobs</name><affiliation><nlm:aff id="aff1"><institution>Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Salomons, Gajja S" sort="Salomons, Gajja S" uniqKey="Salomons G" first="Gajja S" last="Salomons">Gajja S. Salomons</name><affiliation><nlm:aff id="aff1"><institution>Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation></author></analytic><series><title level="j">European Journal of Human Genetics</title><idno type="ISSN">1018-4813</idno><idno type="eISSN">1476-5438</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>The X-linked creatine transporter defect is caused by mutations in the <italic>SLC6A8</italic> gene. Until now, 66 synonymous and intronic variants in <italic>SLC6A8</italic> were detected in our laboratory. To gain more insight in the effect of the detected variants, we applied five free web-based splice-site analysis tools to 25 published variants that were stratified as (non-)disease causing. All were correctly predicted to have no effect (<italic>n</italic>=18) or to cause erroneous splicing (<italic>n</italic>=7), with the exception of a pathogenic <italic>de novo</italic> 24 bp intronic deletion. Second, 41 unclassified variants, including 28 novel, were subjected to analysis by these tools. At least four splice-site analysis tools predicted that three of the variants would affect splicing as the mutations disrupted the canonical splice site. Urinary creatine/creatinine and brain MRS confirmed creatine transporter deficiency in five patients (four families), including one female. Another variant was predicted to moderately affect splicing by all five tools. However, transient transfection of a minigene containing the variant in a partial <italic>SLC6A8</italic> segment showed no splicing errors, and thus was finally classified as non-disease causing. This study shows that splice tools are useful for the characterization of the majority of variants, but also illustrates that the actual effect can be misclassified in rare occasions. Therefore, further laboratory studies should be considered before final conclusions on the disease-causing nature are drawn. To provide an accessible database, the 109 currently known <italic>SLC6A8</italic> variants, including 35 novel ones, are included in a newly developed LOVD DNA variation database.</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">Eur J Hum Genet</journal-id><journal-title-group><journal-title>European Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">1018-4813</issn><issn pub-type="epub">1476-5438</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20717164</article-id><article-id pub-id-type="pmc">3039501</article-id><article-id pub-id-type="pii">ejhg2010134</article-id><article-id pub-id-type="doi">10.1038/ejhg.2010.134</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Characterization of novel <italic>SLC6A8</italic> variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database</article-title><alt-title alt-title-type="running">Analysis of novel <italic>SLC6A8</italic> variants</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Betsalel</surname><given-names>Ofir T</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Rosenberg</surname><given-names>Efraim H</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Almeida</surname><given-names>Ligia S</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Kleefstra</surname><given-names>Tjitske</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Schwartz</surname><given-names>Charles E</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Valayannopoulos</surname><given-names>Vassili</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Abdul-Rahman</surname><given-names>Omar</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Poplawski</surname><given-names>Nicola</given-names></name><xref ref-type="aff" rid="aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Vilarinho</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Wolf</surname><given-names>Philipp</given-names></name><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>den Dunnen</surname><given-names>Johan T</given-names></name><xref ref-type="aff" rid="aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Jakobs</surname><given-names>Cornelis</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Salomons</surname><given-names>Gajja S</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><aff id="aff1"><label>1</label><institution>Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></aff><aff id="aff2"><label>2</label><institution>Department of Pathology, The Netherlands Cancer Institute</institution>, Amsterdam,<country>The Netherlands</country></aff><aff id="aff3"><label>3</label><institution>Medical Genetics Center, National Institute of Health, INSA</institution>, Porto,<country>Portugal</country></aff><aff id="aff4"><label>4</label><institution>Department of Human Genetics, Radboud University Nijmegen Medical Center</institution>, Nijmegen,<country>The Netherlands</country></aff><aff id="aff5"><label>5</label><institution>Greenwood Genetics Center</institution>, Greenwood, SC,<country>USA</country></aff><aff id="aff6"><label>6</label><institution>Department of Metabolic Disorders, Necker-Enfants Malades Hospital</institution>, Paris,<country>France</country></aff><aff id="aff7"><label>7</label><institution>Department of Pediatrics, University of Mississippi Medical Center</institution>, Jackson, MS,<country>USA</country></aff><aff id="aff8"><label>8</label><institution>South Australian Clinical Genetics Service, Women's and Children's Hospital</institution>, North Adelaide, South Australia,<country>Australia</country></aff><aff id="aff9"><label>9</label><institution>Department of Neuropediatrics, DRK Children Clinic Siegen</institution>, Siegen,<country>Germany</country></aff><aff id="aff10"><label>10</label><institution>Department of Human and Clinical Genetics, Leiden University Medical Center</institution>, Leiden,<country>The Netherlands</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label><institution>Department of Clinical Chemistry (Metabolic Unit PK 1 X 009), VU University Medical Center</institution>, De Boelelaan 1117, 1081 HV Amsterdam, <country>The Netherlands</country>. Tel: +31 20 4442738; Fax: +31 20 4440305; E-mail: <email>g.salomons@vumc.nl</email></corresp></author-notes><pub-date pub-type="ppub"><month>01</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>18</day><month>08</month><year>2010</year></pub-date><volume>19</volume><issue>1</issue><fpage>56</fpage><lpage>63</lpage><history><date date-type="received"><day>10</day><month>03</month><year>2010</year></date><date date-type="rev-recd"><day>23</day><month>06</month><year>2010</year></date><date date-type="accepted"><day>24</day><month>06</month><year>2010</year></date></history><permissions><copyright-statement>Copyright © 2011 Macmillan Publishers Limited</copyright-statement><copyright-year>2011</copyright-year><copyright-holder>Macmillan Publishers Limited</copyright-holder></permissions><abstract><p>The X-linked creatine transporter defect is caused by mutations in the <italic>SLC6A8</italic> gene. Until now, 66 synonymous and intronic variants in <italic>SLC6A8</italic> were detected in our laboratory. To gain more insight in the effect of the detected variants, we applied five free web-based splice-site analysis tools to 25 published variants that were stratified as (non-)disease causing. All were correctly predicted to have no effect (<italic>n</italic>=18) or to cause erroneous splicing (<italic>n</italic>=7), with the exception of a pathogenic <italic>de novo</italic> 24 bp intronic deletion. Second, 41 unclassified variants, including 28 novel, were subjected to analysis by these tools. At least four splice-site analysis tools predicted that three of the variants would affect splicing as the mutations disrupted the canonical splice site. Urinary creatine/creatinine and brain MRS confirmed creatine transporter deficiency in five patients (four families), including one female. Another variant was predicted to moderately affect splicing by all five tools. However, transient transfection of a minigene containing the variant in a partial <italic>SLC6A8</italic> segment showed no splicing errors, and thus was finally classified as non-disease causing. This study shows that splice tools are useful for the characterization of the majority of variants, but also illustrates that the actual effect can be misclassified in rare occasions. Therefore, further laboratory studies should be considered before final conclusions on the disease-causing nature are drawn. To provide an accessible database, the 109 currently known <italic>SLC6A8</italic> variants, including 35 novel ones, are included in a newly developed LOVD DNA variation database.</p></abstract><kwd-group><kwd>SLC6A8</kwd><kwd>XLMR</kwd><kwd>splicing</kwd><kwd>LOVD</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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