Congenital Disorder of Glycosylation Type Id: Clinical Phenotype, Molecular Analysis, Prenatal Diagnosis, and Glycosylation of Fetal Proteins

Abstract

Congenital disorder of glycosylation type Id is an inherited glycosylation disorder based on a defect of the first mannosyltransferase involved in N-glycan biosynthesis inside the endoplasmic reticulum. Only one patient with this disease has been described until now. In this article, a second patient and an affected fetus are described. The patient showed abnormal glycosylation of several plasma proteins as demonstrated by isoelectric focusing and Western blot. Lipid-linked oligosaccharides in the endoplasmic reticulum, reflecting early N-glycan assembly, revealed an accumulation of immature Man 5 GlcNAc 2 -glycans in fibroblasts of the patient. Chorion cells of the affected fetus showed the same characteristic lipid-linked oligosaccharides pattern. However, the fetus had a normal glycosylation of several plasma proteins. Some fetal glycoproteins are known to be derived from the mother, but even glycoproteins that do not cross the placenta were normally glycosylated in the affected fetus. Maternal or placental factors that partially compensate for the glycosylation defect in the fetal stage must be proposed and may be relevant for the therapy of these disorders in the future. Inherited defects that affect the biosynthesis of N-or O-glycans are named congenital disorders of glycosylation (CDG) (1). N-linked glycans are attached to asparagine residues of the protein when the Asn occurs within the consensus sequence Asn-X-Ser/Thr. A precursor glycan (Glc 3 Man 9 GlcNAc 2 ) is first assembled in the endoplasmic reticulum on a lipid (dolichol) anchor via a pyrophosphate linkage (Glc 3 Man 9 GlcNAc 2 -PP-dolichol). The glycan is transferred from the anchor to nascent protein and is processed further in the endoplasmic reticulum and Golgi apparatus. O-glycans are attached to serine or threonine residues of the protein via a GalNAc-␣-Ser/Thr linkage and are elongated one sugar at a time; this process occurs in the endoplasmic reticulum and Golgi apparatus. The biochemical compartmentation of the assembly of N-and O-glycans gave rise to the classification of CDG into two subgroups, type I affecting the assembly of the precursor N-glycans on the lipid anchor in the endoplasmic reticulum and type II affecting the processing of the N-glycan after transfer to the protein (2). In recent years, 17 different CDG were characterized, and recently disorders of N-or O-glycosylation that are not yet part of the CDG nomenclature were described (3-5).In 1995, Stibler et al. (6) described two patients with severe psychomotor retardation and an abnormal isoelectric focusing (IEF) pattern of transferrin, suspecting a new subtype of CDG. The biochemical and molecular defect of one patient could subsequently be elucidated by Körner et al. (7), who found a defect in the assembly of lipid-linked oligosaccharides (LLO) in the endoplasmic reticulum of the patient with an accumulation of Man 5 GlcNAc 2 -PP-dolichol. A missense mutation in the human ALG3 gene (8) (synonym: NOT56L, neighbor of tumorous imaginal discs-like protein) coding for doli...

TMEM165 Deficiency: Postnatal Changes in Glycosylation

“…Denecke et al (2005) confirmed that IEF of transferrin in the 19th gestational week was normal in a fetus affected with ALG3-CDG. Other proteins like a1-antitrypsin were also shown to be normally glycosylated in an affected individual in utero.…”

Congenital Disorders of N-Glycosylation Including Diseases Associated With O- as Well as N-Glycosylation Defects

“…More recent patient reports (43)(44)(45) confirm that CDG-1d, apparent from the early weeks of life, is a severe encephalopathy, reminiscent of CDG-Ia and associated with dysmorphic facial and limb features that point at the prenatal expression of this inborn error of metabolism. In one patient the OFC at birth was small (43) and in another it was large (44).…”

“…Denecke et al (44) offer a useful discussion on fetal versus postnatal hypoglycosylation, as the former was shown to be less pronounced in the affected sibling fetus than in their index patient (44). They prove that prenatal diagnosis also of CDG-Id must depend solely on molecular screening of the ALG3 mutations.…”

“…They prove that prenatal diagnosis also of CDG-Id must depend solely on molecular screening of the ALG3 mutations. For details regarding the more recently reported mutant alleles, reading the original reports (41)(42)(43)(44)(45)(46) and consultation of OMIM is recommended.…”

Two Argentinean Siblings with CDG-Ix: A Novel Type of Congenital Disorder of Glycosylation?

“…They were sizefractionated and analyzed by HPLC. Oligosaccharides linked to dolichol were released, extracted, and analyzed by HPLC essentially as described by Denecke et al (2005).…”