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|Title:||Oligosaccharyltransferase-Subunit Mutations in Nonsyndromic Mental Retardation|
|Citation:||American Journal of Human Genetics, 2008; 82(5):1150-1157|
|Publisher:||Univ Chicago Press|
|Florence Molinari, François Foulquier, Patrick S. Tarpey, Willy Morelle, Sarah Boissel, Jon Teague, Sarah Edkins, P. Andrew Futreal, Michael R. Stratton, Gillian Turner, Gert Matthijs, Jozef Gecz, Arnold Munnich and Laurence Colleaux|
|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.|
|Keywords:||Humans; Mental Retardation, X-Linked; Genetic Predisposition to Disease; Hexosyltransferases; Membrane Proteins; Tumor Suppressor Proteins; Protein Subunits; Pedigree; Siblings; Amino Acid Sequence; Glycosylation; Genes, Recessive; Mutation; Molecular Sequence Data; Adult; Female; Male; Intellectual Disability|
|Description:||©2008 by The American Society of Human Genetics. All rights reserved.|
|Appears in Collections:||Paediatrics publications|
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