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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Oligosaccharyltransferase-Subunit Mutations in Nonsyndromic Mental Retardation</title><author><name sortKey="Molinari, Florence" sort="Molinari, Florence" uniqKey="Molinari F" first="Florence" last="Molinari">Florence Molinari</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Foulquier, Francois" sort="Foulquier, Francois" uniqKey="Foulquier F" first="François" last="Foulquier">François Foulquier</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Tarpey, Patrick S" sort="Tarpey, Patrick S" uniqKey="Tarpey P" first="Patrick S." last="Tarpey">Patrick S. Tarpey</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Morelle, Willy" sort="Morelle, Willy" uniqKey="Morelle W" first="Willy" last="Morelle">Willy Morelle</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Boissel, Sarah" sort="Boissel, Sarah" uniqKey="Boissel S" first="Sarah" last="Boissel">Sarah Boissel</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Teague, Jon" sort="Teague, Jon" uniqKey="Teague J" first="Jon" last="Teague">Jon Teague</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Edkins, Sarah" sort="Edkins, Sarah" uniqKey="Edkins S" first="Sarah" last="Edkins">Sarah Edkins</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Futreal, P Andrew" sort="Futreal, P Andrew" uniqKey="Futreal P" first="P. Andrew" last="Futreal">P. Andrew Futreal</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R." last="Stratton">Michael R. Stratton</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Turner, Gillian" sort="Turner, Gillian" uniqKey="Turner G" first="Gillian" last="Turner">Gillian Turner</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Matthijs, Gert" sort="Matthijs, Gert" uniqKey="Matthijs G" first="Gert" last="Matthijs">Gert Matthijs</name><affiliation><nlm:aff id="aff2"></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="aff6"></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Colleaux, Laurence" sort="Colleaux, Laurence" uniqKey="Colleaux L" first="Laurence" last="Colleaux">Laurence Colleaux</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">18455129</idno><idno type="pmc">2427205</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2427205</idno><idno type="RBID">PMC:2427205</idno><idno type="doi">10.1016/j.ajhg.2008.03.021</idno><date when="2008">2008</date><idno type="wicri:Area/Pmc/Corpus">001702</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001702</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Oligosaccharyltransferase-Subunit Mutations in Nonsyndromic Mental Retardation</title><author><name sortKey="Molinari, Florence" sort="Molinari, Florence" uniqKey="Molinari F" first="Florence" last="Molinari">Florence Molinari</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Foulquier, Francois" sort="Foulquier, Francois" uniqKey="Foulquier F" first="François" last="Foulquier">François Foulquier</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Tarpey, Patrick S" sort="Tarpey, Patrick S" uniqKey="Tarpey P" first="Patrick S." last="Tarpey">Patrick S. Tarpey</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Morelle, Willy" sort="Morelle, Willy" uniqKey="Morelle W" first="Willy" last="Morelle">Willy Morelle</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Boissel, Sarah" sort="Boissel, Sarah" uniqKey="Boissel S" first="Sarah" last="Boissel">Sarah Boissel</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Teague, Jon" sort="Teague, Jon" uniqKey="Teague J" first="Jon" last="Teague">Jon Teague</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Edkins, Sarah" sort="Edkins, Sarah" uniqKey="Edkins S" first="Sarah" last="Edkins">Sarah Edkins</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Futreal, P Andrew" sort="Futreal, P Andrew" uniqKey="Futreal P" first="P. Andrew" last="Futreal">P. Andrew Futreal</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R." last="Stratton">Michael R. Stratton</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Turner, Gillian" sort="Turner, Gillian" uniqKey="Turner G" first="Gillian" last="Turner">Gillian Turner</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Matthijs, Gert" sort="Matthijs, Gert" uniqKey="Matthijs G" first="Gert" last="Matthijs">Gert Matthijs</name><affiliation><nlm:aff id="aff2"></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="aff6"></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Colleaux, Laurence" sort="Colleaux, Laurence" uniqKey="Colleaux L" first="Laurence" last="Colleaux">Laurence Colleaux</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="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Mental retardation (MR) is the most frequent handicap among children and young adults. Although a large proportion of X-linked MR genes have been identified, only four genes responsible for autosomal-recessive nonsyndromic MR (AR-NSMR) have been described so far. Here, we report on two genes involved in autosomal-recessive and X-linked NSMR. First, autozygosity mapping in two sibs born to first-cousin French parents led to the identification of a region on 8p22-p23.1. This interval encompasses the gene <italic>N33/TUSC3</italic> encoding one subunit of the oligosaccharyltransferase (OTase) complex, which catalyzes the transfer of an oligosaccharide chain on nascent proteins, the key step of N-glycosylation. Sequencing <italic>N33/TUSC3</italic> identified a 1 bp insertion, c.787_788insC, resulting in a premature stop codon, p.N263fsX300, and leading to mRNA decay. Surprisingly, glycosylation analyses of patient fibroblasts showed normal N-glycan synthesis and transfer, suggesting that normal N-glycosylation observed in patient fibroblasts may be due to functional compensation. Subsequently, screening of the X-linked <italic>N33/TUSC3</italic> paralog, the <italic>IAP</italic> gene, identified a missense mutation (c.932T→G, p.V311G) in a family with X-linked NSMR. Recent studies of fucosylation and polysialic-acid modification of neuronal cell-adhesion glycoproteins have shown the critical role of glycosylation in synaptic plasticity. However, our data provide the first demonstration that a defect in N-glycosylation can result in NSMR. Together, our results demonstrate that fine regulation of OTase activity is essential for normal cognitive-function development, providing therefore further insights to understand the pathophysiological bases of MR.</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>American Society of Human Genetics</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18455129</article-id><article-id pub-id-type="pmc">2427205</article-id><article-id pub-id-type="publisher-id">AJHG143</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2008.03.021</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Oligosaccharyltransferase-Subunit Mutations in Nonsyndromic Mental Retardation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Molinari</surname><given-names>Florence</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Foulquier</surname><given-names>François</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Tarpey</surname><given-names>Patrick S.</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Morelle</surname><given-names>Willy</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Boissel</surname><given-names>Sarah</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Teague</surname><given-names>Jon</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Edkins</surname><given-names>Sarah</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Futreal</surname><given-names>P. Andrew</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Stratton</surname><given-names>Michael R.</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Turner</surname><given-names>Gillian</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Matthijs</surname><given-names>Gert</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Gecz</surname><given-names>Jozef</given-names></name><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Munnich</surname><given-names>Arnold</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Colleaux</surname><given-names>Laurence</given-names></name><email>colleaux@necker.fr</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>Laboratoire de Génétique et Epigénétique des Maladies Métaboliques, Neurosensorielles et du Développement (INSERM U781), Université Paris Descartes, Hôpital Necker-Enfants Malades, F-75015 Paris, France</addr-line></aff><aff id="aff2"><addr-line><sup>2</sup>Laboratory for Molecular Diagnostics, Center for Human Genetics, University of Leuven, 3000 B-Leuven, Belgium</addr-line></aff><aff id="aff3"><addr-line><sup>3</sup>Unité Mixte de Recherche CNRS/USTL 8576, Glycobiologie Structurale et Fonctionnelle, IFR 147, Université des Sciences et Technologies de Lille 1, F-59655 Villeneuve d'Ascq, France</addr-line></aff><aff id="aff4"><addr-line><sup>4</sup>Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA Cambridge, UK</addr-line></aff><aff id="aff5"><addr-line><sup>5</sup>The Gold Service, Hunter Genetics and University of Newcastle, New South Wales, NSW 2308, Australia</addr-line></aff><aff id="aff6"><addr-line><sup>6</sup>Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, SA 5005, Australia</addr-line></aff><aff id="aff7"><addr-line><sup>7</sup>Department of Pediatrics and School of Molecular & Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia</addr-line></aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>colleaux@necker.fr</email></corresp></author-notes><pub-date pub-type="ppub"><day>09</day><month>5</month><year>2008</year></pub-date><pub-date pub-type="epub"><day>02</day><month>5</month><year>2008</year></pub-date><volume>82</volume><issue>5</issue><fpage>1150</fpage><lpage>1157</lpage><history><date date-type="received"><day>20</day><month>12</month><year>2007</year></date><date date-type="rev-recd"><day>12</day><month>3</month><year>2008</year></date><date date-type="accepted"><day>16</day><month>3</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>Mental retardation (MR) is the most frequent handicap among children and young adults. Although a large proportion of X-linked MR genes have been identified, only four genes responsible for autosomal-recessive nonsyndromic MR (AR-NSMR) have been described so far. Here, we report on two genes involved in autosomal-recessive and X-linked NSMR. First, autozygosity mapping in two sibs born to first-cousin French parents led to the identification of a region on 8p22-p23.1. This interval encompasses the gene <italic>N33/TUSC3</italic> encoding one subunit of the oligosaccharyltransferase (OTase) complex, which catalyzes the transfer of an oligosaccharide chain on nascent proteins, the key step of N-glycosylation. Sequencing <italic>N33/TUSC3</italic> identified a 1 bp insertion, c.787_788insC, resulting in a premature stop codon, p.N263fsX300, and leading to mRNA decay. Surprisingly, glycosylation analyses of patient fibroblasts showed normal N-glycan synthesis and transfer, suggesting that normal N-glycosylation observed in patient fibroblasts may be due to functional compensation. Subsequently, screening of the X-linked <italic>N33/TUSC3</italic> paralog, the <italic>IAP</italic> gene, identified a missense mutation (c.932T→G, p.V311G) in a family with X-linked NSMR. Recent studies of fucosylation and polysialic-acid modification of neuronal cell-adhesion glycoproteins have shown the critical role of glycosylation in synaptic plasticity. However, our data provide the first demonstration that a defect in N-glycosylation can result in NSMR. Together, our results demonstrate that fine regulation of OTase activity is essential for normal cognitive-function development, providing therefore further insights to understand the pathophysiological bases of MR.</p></abstract></article-meta></front><floats-wrap><fig id="fig1"><label>Figure 1</label><caption><p>Genetic Analysis of Family 1</p><p>(A) Pedigree of family 1. The black symbols indicate the affected individuals. Autozygosity mapping was performed with Affymetrix GeneChip Human Mapping 10K for individuals IV.3, IV.4, and V.1 to V.4. Haplotypes are shown beneath each genotyped individual. Markers are from telomere to centromere, and their positions, based on the UCSC Genome browser, are indicated in bp.</p><p>(B) Electropherograms of <italic>N33/TUSC3</italic> exon 6 in an affected patient (left) and a control (right). DNA sequencing identified a one base-pair homozygous insertion c.787_788insC.</p><p>(C) N33/TUSC3 mutation and phylogenetic analysis of N33/TUSC3 proteins in various species. Amino acids are in italics; bold and underlined indicate the frame shift caused by <italic>N33/TUSC3</italic> mutation.</p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Quantitative PCR Analysis of <italic>N33/TUSC3</italic> mRNA</p><p><italic>N33/TUSC3</italic> expression in fibroblasts from two controls (black and white bars) and patient V.1 (gray bar). Data are normalized to <italic>Beta-actin</italic> (<italic>ACTB</italic>) or <italic>Vimentin</italic> (<italic>Vim</italic>). Means are given ± standard deviation (n = 4 to 8 independent RT-PCR). <sup>∗∗∗</sup>, p < 0.001 as compared to controls, Student's t test.</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>MALDI-TOF MS Analysis of Total Human Serum N-Glycome</p><p>(A) Spectrum obtained from of a normal individual.</p><p>(B and C) Spectra obtained from the two affected children of family 1, V.4 and V.1, respectively. Only the structures of the major N-glycans are given. A minor portion of the monofucosylated glycans carries fucose on an antenna rather than the core. Galactose (open circles), mannose (closed circles), GlcNAc (closed squares), fucose (open triangles), and NeuAc (closed diamonds) are shown.</p><p>(D) Incorporation of [2-<sup>3</sup>H]mannose and [<sup>35</sup>S]methionine was determined after metabolic labeling of fibroblasts for 20, 40, and 60 min. Shown is the average ratio of [<sup>35</sup>S]methionine versus [2-<sup>3</sup>H]mannose incorporation into proteins of two independent experiments.</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Genetic Analysis of Family 2</p><p>(A) Pedigree of family 2. The black symbols indicate individuals presenting severe MR, the white and black symbols indicate individuals presenting mild MR, and the white symbols indicate the nonaffected individuals. Carriers of mutated (mut) or wild-type (wt) alleles are indicated.</p><p>(B) Electropherograms of <italic>IAP</italic> exon 9 in one affected boy of family 2 (left) and a control (right). DNA sequencing identified a missense mutation c.932T→G.</p><p>(C) IAP mutation and phylogenetic analysis of IAP proteins in various species. The arrow and bold amino acids indicate the substitution caused by the mutation.</p></caption><graphic xlink:href="gr4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Expression Analyses of <italic>N33/TUSC3</italic>, <italic>IAP</italic>, and <italic>Vimentin</italic></p><p>Expression was asseyed by RT-PCR on adult and fetal total RNA isolated from various tissues (Clontech): fetal liver (F.liv), heart, kidney (Kid.), adult liver (Ad.liv), lung, placenta (Pl.), prostate (Pr.), salivary gland (Sal.g), skeletal muscle (Sk.m), testis, thymus, thyroid gland (Thyr.g), trachea (Tr.), uterus (Ut.), fetal chondrocytes (F.ch), and osteoblasts (Ost.). Amplicon length of <italic>N33/TUSC3</italic>, <italic>IAP</italic>, and <italic>Vimentin</italic> (<italic>Vim</italic>) are indicated in bp.</p></caption><graphic xlink:href="gr5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>Expression Analyses of <italic>N33/TUSC3</italic>, <italic>IAP</italic>, and <italic>Vimentin</italic> (<italic>Vim</italic>) mRNAs in Adult and Fetal Brain Structures</p><p>Expression was tested by RT-PCR on adult and fetal structures (Clontech): adrenal gland (Adr.g), bone marrow (B.m), cerebellum (Cer.), adult brain (Ad.brain), fetal brain (F.brain), spinal cord (Sp.c), hippocampus (Hipp.), and cortex (Cx). Amplicon length of <italic>N33/TUSC3</italic>, <italic>IAP</italic>, and <italic>Vimentin</italic> (<italic>Vim</italic>) are indicated in bp.</p></caption><graphic xlink:href="gr6"></graphic></fig></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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