Deficiency of UDP-galactose:N-acetylglucosamine β-1,4-galactosyltransferase I causes the congenital disorder of glycosylation type IId

Bengt Hanßke,Martin Hasilik,Verena Peters,Peter H Heidemann,Torben Lübke,Christian Thiel,Kurt Von Figura,Georg F Hoffmann,Stefan Höning,Christian Körner,Eric G Berger

doi:10.1172/jci0214010

Abstract

Deficiency of the Golgi enzyme UDP-Gal:N-acetylglucosamine β-1,4-galactosyltransferase I (β4GalT I) (E.C.2.4.1.38) causes a new congenital disorder of glycosylation (CDG), designated type IId (CDG-IId), a severe neurologic disease characterized by a hydrocephalus, myopathy, and blood-clotting defects. Analysis of oligosaccharides from serum transferrin by HPLC, mass spectrometry, and lectin binding revealed the loss of sialic acid and galactose residues. In skin fibroblasts and leukocytes, galactosyltransferase activity was reduced to 5% that of controls. In fibroblasts, a truncated polypeptide was detected that was about 12 kDa smaller in size than wild-type β4GalT I and that failed to localize to the Golgi apparatus. Sequencing of the β4GalT I cDNA and gene revealed an insertion of a single nucleotide (1031-1032insC) leading to premature translation stop and loss of the C-terminal 50 amino acids of the enzyme. The patient was homozygous and his parents heterozygous for this mutation. Expression of a corresponding mutant cDNA in COS-7 cells led to the synthesis of a truncated, inactive polypeptide, which localized to the endoplasmic reticulum.

Highlights

The congenital disorders of glycosylation (CDGs) comprise a rapidly growing group of inherited multisystemic disorders that are commonly associated with severe psychomotor and mental retardation
The hyposialylated transferrin from CDG patients shows a cathodic shift, which in CDG-I is due to the loss of either one or both oligosaccharides and in CDG-II is due to the incomplete processing of protein-bound oligosaccharides
The diagnosis of CDG in patient M.S. was indicated by isoelectric focusing (IEF) of serum transferrin [19]

Summary

Introduction

The congenital disorders of glycosylation (CDGs) comprise a rapidly growing group of inherited multisystemic disorders that are commonly associated with severe psychomotor and mental retardation. The characteristic biochemical feature of CDGs is the defective glycosylation of glycoproteins due to mutations in genes required for the biosynthesis of N-linked oligosaccharides. Defects of the assembly of lipidlinked oligosaccharides or their transfer onto nascent glycoproteins form type I of CDG, whereas CDG type II comprises all defects of trimming and elongating of N-linked oligosaccharides [1]. N-glycosylation defects are routinely detected by isoelectric focusing (IEF) of serum transferrin, which normally carries two sialylated biantennary N-linked oligosaccharides. The hyposialylated transferrin from CDG patients shows a cathodic shift, which in CDG-I is due to the loss of either one or both oligosaccharides and in CDG-II is due to the incomplete processing of protein-bound oligosaccharides. In the past six years the molecular nature of six CDG-I and three CDG-II types has been described [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]

Methods

Results

Conclusion