TY - JOUR
T1 - Oligosaccharyltransferase-Subunit Mutations in Nonsyndromic Mental Retardation
AU - Molinari, Florence
AU - Foulquier, François
AU - Tarpey, Patrick S.
AU - Morelle, Willy
AU - Boissel, Sarah
AU - Teague, Jon
AU - Edkins, Sarah
AU - Futreal, P. Andrew
AU - Stratton, Michael R.
AU - Turner, Gillian
AU - Matthijs, Gert
AU - Gecz, Jozef
AU - Munnich, Arnold
AU - Colleaux, Laurence
N1 - Funding Information:
We are thankful to J. Chelly for providing us with samples of 18 boys with XLMR, to J.P. Jais for LOD score calculation, and to the patients and families for their cooperation. We also want to thank M. Aebi for sharing unpublished data regarding the functional analyses of yeast Ost3 and Ost6 genes and for helpful discussion. This study was supported in part by the Centre National de la Recherche Scientifique (CNRS), the Agence Nationale de la Recherche (ANR), the Ministère de la Recherche et de l'Enseignement Supérieur (France), the Fund for Scientific Research (Flanders, Belgium), and Mizutani Foundation for Glycoscience (Japan). The Mass Spectrometry facility used in this study was funded by the European Community (FEDER), the Région Nord-Pas de Calais (France), and the Université des Sciences et Technologies de Lille I.
PY - 2008/5/9
Y1 - 2008/5/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=42749084689&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2008.03.021
DO - 10.1016/j.ajhg.2008.03.021
M3 - Article
C2 - 18455129
AN - SCOPUS:42749084689
SN - 0002-9297
VL - 82
SP - 1150
EP - 1157
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -