Oligosaccharyltransferase-Subunit Mutations in Nonsyndromic Mental Retardation

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, Laurence Colleaux

Research output: Contribution to journalArticlepeer-review

126 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1150-1157
Number of pages8
JournalAmerican Journal of Human Genetics
Volume82
Issue number5
DOIs
Publication statusPublished or Issued - 9 May 2008
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this