Oligosaccharyltransferase-Subunit Mutations in Nonsyndromic Mental Retardation

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.

Homozygous Truncating Intragenic Duplication in TUSC3 Responsible for Rare Autosomal Recessive Nonsyndromic Intellectual Disability with No Clinical or Biochemical Metabolic Markers

“…(c) Nucleotide sequence of the chr8:15432761-15423779 region analyzed with Human Splicing Finder-underlined, branch site, splice acceptor site, and splice donor site consensus sequences; in italics, CT-rich region; in bold, predicted ESE; in gray, 95 bp intergenic included region Table 2. Among the patients who had brain imaging, only one had brain abnormalities (hypertensive hydrocephalus, surgically treated at age 3 months, and mild enlargement of the frontal subarachnoid spaces and ventricles on the follow-up brain MRI) and none of them had the cerebellar abnormalities classically described in CDG (Table 2) (Molinari et al 2008;Garshasbi et al 2008Garshasbi et al , 2011Khan et al 2011;Loddo et al 2013). The majority of patients (16 patients, 4 families) were identified by array-CGH analysis (Table 2).…”

“…The majority of patients (16 patients, 4 families) were identified by array-CGH analysis (Table 2). Other families were identified by homozygosity mapping and direct sequencing of TUSC3 (Molinari et al 2008;Garshasbi et al 2008Garshasbi et al , 2011Khan et al 2011;Loddo et al 2013) (Fig. 3).…”

“…Two mammalian OTase complexes composed of seven proteins differ by the presence of TUSC3 or IAP proteins (Kelleher and Gilmore 2006). TUSC3 appears ubiquitously expressed with greater expression in the fetal brain (Molinari et al 2008) and interacts with the alpha isoform of the protein phosphatase 1 (PPPC1A; OMIM176875) catalytic subunit, which is involved in the modulation of synaptic plasticity, and in memory and learning processes in mice (Garshasbi et al 2008). TUSC3 has also been implicated in the Mg2+ membrane transport system with a possible role in learning capacities, working memory, and short-and long-term memory.…”

“…Reported patients with TUSC3 mutations have normal results of glycosylation analyses, which could be explained by the compensation, at least partially in a tissue-specific manner, of TUSC3 by IAP, the TUSC3 paralog, coding for an OTase subunit and known to be involved in the N-glycosylation process (Kelleher et al 2003;Garshasbi et al 2008;Molinari et al 2008). Another hypothesis would be that TUSC3 and IAP protein function is essential for the glycosylation of proteins belonging to cellular subgroups in a specific tissue, mainly the central nervous system, which cannot be explored by usual serum glycosylation screening techniques.…”

A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype

“…26 Moreover, TUSC3-CDG and MAGT1-CDG are implicated in non-syndromic ID patients, with the age range of 25-62 years. 27 It can be anticipated that other CDG-I subtypes will be associated with mild/moderate phenotypes as well and that mutations in CDG-I genes might be more common than thought until now.…”