- Title
- Oligosaccharyltransferase-subunit mutations in nonsyndromic mental retardation
- Creator
- Molinari, Florence; Foulquier, François; Matthijs, Gert; Gecz, Jozef; Munnich, Arnold; Colleaux, Laurence; Tarpey, Patrick S.; Morelle, Willy; Boissel, Sarah; Teague, Jon; Edkins, Sarah; Futreal, P. Andrew; Stratton, Michael R.; Turner, Gillian
- Relation
- American Journal of Human Genetics Vol. 82, Issue 5, p. 1150-1157
- Publisher Link
- http://dx.doi.org/10.1016/j.ajhg.2008.03.021
- Publisher
- Elsevier
- Resource Type
- journal article
- Date
- 2008
- Description
- 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.
- Subject
- mental retardation (MR); X-linked; oligosaccharyltransferase; cognitive function development
- Identifier
- uon:5122
- Identifier
- http://hdl.handle.net/1959.13/42988
- Identifier
- ISSN:0002-9297
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