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Title: Oligosaccharyltransferase-subunit mutations in nonsyndromic mental retardation
Authors: Molinari, Florence ×
Foulquier, Fran├žois
Tarpey, Patrick S
Morelle, Willy
Boissel, Sarah
Teague, Jon
Edkins, Sarah
Futreal, P Andrew
Stratton, Michael R
Turner, Gillian
Matthijs, Gert
Gecz, Jozef
Munnich, Arnold
Colleaux, Laurence #
Issue Date: May-2008
Series Title: American Journal of Human Genetics vol:82 issue:5 pages:1150-1157
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.
URI: 
ISSN: 0002-9297
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical Genetics Section (-)
Laboratory for Molecular Diagnosis
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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