DDOST mutations identified by whole-exome sequencing are implicated in congenital disorders of glycosylation.
Congenital disorders of glycosylation (CDG) are inherited autosomal-recessive diseases that impair N-glycosylation. Approximately 20% of patients do not survive beyond the age of 5 years old as a result of widespread organ dysfunction. Although most patients receive a CDG diagnosis based on abnormal glycosylation of transferrin, this test cannot provide a genetic diagnosis; indeed, many patients with abnormal transferrin do not have mutations in any known CDG genes. Here, we combined biochemical analysis with whole-exome sequencing (WES) to identify the genetic defect in an untyped CDG patient, and we found a 22 bp deletion and a missense mutation in DDOST, whose product is a component of the oligosaccharyltransferase complex that transfers the glycan chain from a lipid carrier to nascent proteins in the endoplasmic reticulum lumen. Biochemical analysis with three biomarkers revealed that N-glycosylation was decreased in the patient's fibroblasts. Complementation with wild-type-DDOST cDNA in patient fibroblasts restored glycosylation, indicating that the mutations were pathological. Our results highlight the power of combining WES and biochemical studies, including a glyco-complementation system, for identifying and confirming the defective gene in an untyped CDG patient. This approach will be very useful for uncovering other types of CDG as well.
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Melanie A
MA
Jones
Bobby G
BG
Ng
Shruti
S
Bhide
Ephrem
E
Chin
Devin
D
Rhodenizer
Ping
P
He
Marie-Estelle
ME
Losfeld
Miao
M
He
Kimiyo
K
Raymond
Gerard
G
Berry
Hudson H
HH
Freeze
Madhuri R
MR
Hegde
D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D018981:Congenital Disorders of Glycosylation / Q000201:enzymology / Q000235:genetics*; D059472:Exome; D005347:Fibroblasts / Q000378:metabolism; D006031:Glycosylation; D006602:Hexosyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D014168:Transferrin / Q000378:metabolism
D015415:Biomarkers; D008565:Membrane Proteins; D014168:Transferrin; D006602:Hexosyltransferases; C025620:dolichyl-diphosphooligosaccharide - protein glycotransferase