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0031-3998/06/6006-0643 PEDIATRIC RESEARCH Copyright © 2006 International Pediatric Research Foundation, Inc.

Vol. 60, No. 6, 2006 Printed in U.S.A.

REVIEW ARTICLE Congenital Disorders of N-Glycosylation Including Diseases Associated With O- as Well as N-Glycosylation Defects
JULES G. LEROY Departments of Pediatrics and Medical Genetics, Ghent University School of Medicine and UniversityHospital, B-9000 Ghent, Belgium ABSTRACT: The congenital disorders of N-glycosylation (CDG), a steadily increasing group of multi-systemic disorders, have severe clinical implications in infancy and early childhood. The various inborn errors responsible adversely affect N-glycosylation of lysosomal proteins because of either failing assembly of lipid-linked (LL) oligosaccharides (OS) in theendoplasmic reticulum, CDG Type I, or faulty processing of the asparagines (N)-linked OS in the ER and in the Golgi, CDG Type II. The overlap of phenotypes precludes specific clinical delineation. Isoelectric focusing (IEF) of plasma transferrin remains a valuable, albeit imperfect, screening tool. IEF of plasma ApoC-III protein, introduced O-glycosylation defects that delineated some new CDGs due tomutations of both N- and Oglycosylation. Only CDG-Ib is amenable to treatment with free mannose supplementation. Hence, early specific diagnosis of any one entity is crucial for genetic counseling and elective preventive measures. (Pediatr Res 60: 643–656, 2006)

and follow a divergent course in the Golgi cisterns. The Golgi apparatus is the intracellular site of O-glycosylation, a sequentialpost-translational process. N-GLYCOSYLATION DEFICIENCY SYNDROMES DUE TO OS ASSEMBLY DEFECTS N-glycosylation of proteins is conserved in eukaryotes. Oligosaccharide (OS)-type glycans are N-linked to proteins by the covalent amide bond between asparagine (Asn) in specific amino acid sequences (called sequons) in the nascent polypeptides, and the N-acetylglucosamine (GlcNAc) residue at their reducing end. Theoligosaccharide to be transferred to nascent polypeptides is assembled in a step-by-step fashion while linked to dolichyl-phosphate (Dol-P-), an oligoisoprenyl type phosphorylated lipid, embedded in the ER membrane. Most of the already delineated congenital disorders of N-glycosylation are the result of mutations in genes encoding enzymes catalyzing either a monosaccharide interconversion oractivation step, or functioning as monosaccharide transferases in the OS assembly. Because the defects result in hypoglycosylation of proteins, they are associated with a common abnormal profile obtained by plasma transferrin (Tf) isoelectric focusing (IEF) called the Type I Tf-IEF profile. The disorders associated with it are termed CDG-Type I. The Type II Tf-IEF profile is an inconsistent feature ofthe second group of CDGs as in half of them the normal plasma Tf-IEF profile is obtained. A few newly characterized types of CDG-II are associated with abnormal intra-Golgi enzyme distribution and their ineffective and uncoordinated action of deficient N- as well as Oglycosylation is the result. Co-Translational Assembly of the Major OS; Transfer to Nascent Proteins N-glycosylation has been studiedextensively in the budding yeast, Saccharomyces cerevisiae (S. cer.). Findings in
Abbreviations: CDG, congenital disorder of glycosylation; CHO cells, Chinese hamster ovary cells; CMP, cytidine monophosphate; COG, complex conserved oligomeric Golgi complex; (DD-) OST, (dolichyl-diphospho-) oligosaccharide protein glycosyl transferase; Dol-P (-PP), dolichyl-phosphate (-pyrophosphate); GDP,guanosinediphosphate; GlcNAc, N-acetylglucosamine; IEF, isoelectric focusing; MIM, Mendelian inheritance in man; OS, oligosaccharide; Tf, transferrin; UDP, uridinediphosphate 643

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he multi-system disorders previously termed the carbohydrate-deficient glycoprotein syndromes have been renamed congenital disorders of glycosylation (CDGs) (1). In most, either the assembly or the processing of N-linked...