A new congenital disorder of glycosylation caused by a mutation in SSR4, the signal sequence receptor 4 protein of the TRAP complex

• DOI: 10.1093/hmg/ddt550
• Publication Date: 2013-11-12T02:23:29Z
• Authors: M. E. Losfeld; B. G. Ng; M. Kircher; K. J. Buckingham; E. H. Turner; A. Eroshkin; J. D. Smith; J. Shendure; D. A. Nickerson; M. J. Bamshad; ; H. H. Freeze
• Keywords: Male; 0301 basic medicine; Chromosomes, Human, X; Glycosylation; Membrane Glycoproteins; Adolescent; Receptors, Peptide; Calcium-Binding Proteins; Receptors, Cytoplasmic and Nuclear; 03 medical and health sciences; Congenital Disorders of Glycosylation; Humans; Point Mutation; Cells, Cultured

Nearly 50 congenital disorders of glycosylation (CDG) are known, but many patients biochemically diagnosed with CDG do not have mutations in known genes. Here, we describe a 16-year-old male who was born with microcephaly, developed intellectual disability, gastroesophageal reflux and a seizure disorder. We identified a de novo variant in the X-linked SSR4 gene which encodes a protein of the heterotetrameric translocon-associated protein (TRAP) complex. The c.316delT causes a p.F106Sfs*53 in SSR4 and also reduces expression of other TRAP complex proteins. The glycosylation marker Glyc-ER-GFP was used to confirm the underglycosylation in fibroblasts from the patient. Overexpression of the wild-type SSR4 allele partially restores glycosylation of the marker and of the other members of the TRAP complex. This is the first evidence that the TRAP complex, which binds to the oligosaccharyltransferase complex, is directly involved in N-glycosylation.