A new congenital disorder of glycosylation caused by a mutation in SSR4, the signal sequence receptor 4 protein of the TRAP complex.
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.
Genetic Disease Program, Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Marie Estelle
ME
Losfeld
Bobby G
BG
Ng
Martin
M
Kircher
Kati J
KJ
Buckingham
Emily H
EH
Turner
Alexey
A
Eroshkin
Joshua D
JD
Smith
Jay
J
Shendure
Deborah A
DA
Nickerson
Michael J
MJ
Bamshad
Hudson H
HH
Freeze
D000293:Adolescent; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002478:Cells, Cultured; D041321:Chromosomes, Human, X; D018981:Congenital Disorders of Glycosylation / Q000235:genetics* / Q000473:pathology; D006031:Glycosylation; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D017354:Point Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*
D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D018000:Receptors, Peptide; C066973:signal sequence receptor