Molecular Diagnosis of Congenital Disorders of Glycosylation

Abstract

Congenital disorders of glycosylation (CDG) represent a group of diseases affecting N-linked glycosylation pathways and require structural analysis of glycoproteins or their glycans for decisive diagnosis. CDG are classified into two groups: the classical type of CDG (CDG-I) results from deficiencies in the early glycosylation pathway for biosynthesis of lipid-linked oligosaccharide and its transfer to proteins in endoplasmic reticulum, while the CDG-II diseases are caused by defects in the subsequent processing steps. Different types of disorders in each class are indicated by a small letter code (a, b, c, etc.) consistent with the chronological order in which the defective gene was identified, and 18 disorders have been documented to date (Freeze and Aebi 2005). Isoelectric focusing (IEF) of serum transferrin (Tf) has been used for laboratory screening of CDG. Serum Tf has two disialo-biantennary N-glycans as the major oligosaccharide at Asn-432 and Asn-630, and a defect in the glycan moiety accompanies sialic acid deficiency causing a shift of the protein pI values. Recently, mass spectrometry (MS) has been utilized to detect a change in the molecular mass by 2,200 Da per glycan set in CDG-I or a smaller change due to the glycan processing defects in CDG-II. A program for molecular diagnosis has started in Japan according to the protocols in Scheme 1 (Wada 2006).