Congenital disorder of glycosylation caused by a mutation in SSR4, the signal sequence receptor 4 protein of the TRAP complex (789.3)

Congenital Disorders of Glycosylation (CDG) are a family of genetic disorders affecting the glycosylation pathway or the trafficking of glycoproteins. Nearly 50 genes causing CDG have been described, but many patients biochemically diagnosed with CDG do not have mutations in known genes. Among our CDG patients, we identified by exome saequencing, in three patients, new variants of the X-linked SSR4 gene which encodes a protein of the heterotetrameric translocon-associated protein (TRAP) complex. Two of these variants results in the absence of SSR4 expression. In these cases, we observed that expression of other TRAP complex proteins was also reduced. The glycosylation marker Glyc-ER-GFP was used to confirm the underglycosylation in fibroblasts from patients. Over-expression of the wild type SSR4 allele partially restores glycosylation of the marker and expression of the other members of the TRAP complex. This is the first evidence that the TRAP complex, which binds to the oligosaccharyltransferase complex...