Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 5, 1150-1157, 01 May 2008
doi:10.1016/j.ajhg.2008.03.021
Article
Oligosaccharyltransferase-Subunit Mutations in Nonsyndromic Mental Retardation
Florence Molinari1, François Foulquier2, 3, Patrick S. Tarpey4, Willy Morelle3, Sarah Boissel1, Jon Teague4, Sarah Edkins4, P. Andrew Futreal4, Michael R. Stratton4, Gillian Turner5, Gert Matthijs2, Jozef Gecz6, 7, Arnold Munnich1 and Laurence Colleaux1, 
, 
1 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
2 Laboratory for Molecular Diagnostics, Center for Human Genetics, University of Leuven, 3000 B-Leuven, Belgium
3 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
4 Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA Cambridge, UK
5 The Gold Service, Hunter Genetics and University of Newcastle, New South Wales, NSW 2308, Australia
6 Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, SA 5005, Australia
7 Department of Pediatrics and School of Molecular & Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia
Corresponding authorAbstract
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 N33/TUSC3 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 N33/TUSC3 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 N33/TUSC3 paralog, the IAP 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.
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