title: Oligosaccharyltransferase-subunit mutations in nonsyndromic mental retardation.
abstract: 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.
authors.affiliation: 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.
authors.forename: Florence
authors.initials: F
authors.lastname: Molinari
authors.forename: François
authors.initials: F
authors.lastname: Foulquier
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Tarpey
authors.forename: Willy
authors.initials: W
authors.lastname: Morelle
authors.forename: Sarah
authors.initials: S
authors.lastname: Boissel
authors.forename: Jon
authors.initials: J
authors.lastname: Teague
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Gillian
authors.initials: G
authors.lastname: Turner
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D006602:Hexosyltransferases / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D038901:X-Linked Intellectual Disability / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D021122:Protein Subunits / Q000235:genetics; D035781:Siblings; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D021122:Protein Subunits; C524338:TUSC3 protein, human; D025521:Tumor Suppressor Proteins; D006602:Hexosyltransferases; C025620:dolichyl-diphosphooligosaccharide - protein glycotransferase