Deficiency of GDP-Man:GlcNAc2-PP-Dolichol Mannosyltransferase Causes Congenital Disorder of Glycosylation Type Ik

Abstract

The molecular nature of a severe multisystemic disorder with a recurrent nonimmune hydrops fetalis was identified as deficiency of GDP-Man:GlcNAc(2)-PP-dolichol mannosyltransferase, the human orthologue of the yeast ALG1 gene (MIM 605907). The disease belongs to the group of congenital disorders of glycosylation (CDG) and is designated as subtype CDG-Ik. In patient-derived serum, the total amount of the glycoprotein transferrin was reduced. Moreover, a partial loss of N-glycan chains was observed, a characteristic feature of CDG type I forms. Metabolic labeling with [6-(3)H]glucosamine revealed an accumulation of GlcNAc(2)-PP-dolichol and GlcNAc(1)-PP-dolichol in skin fibroblasts of the patient. Incubation of fibroblast extracts with [(14)C]GlcNAc(2)-PP-dolichol and GDP-mannose indicated a severely reduced activity of the beta 1,4-mannosyltransferase, elongating GlcNAc(2)-PP-dolichol to Man(1)GlcNAc(2)-PP-dolichol at the cytosolic side of the endoplasmic reticulum. Genetic analysis of the patient's hALG1 gene identified a homozygous mutation leading to the exchange of a serine residue to leucine at position 258 in the hALG1 protein. The disease-causing nature of the hALG1 mutation for the glycosylation defect was verified by a retroviral complementation approach in patient-derived primary fibroblasts and was confirmed by the expression of wild-type and mutant hALG1 in the Saccharomyces cerevisiae alg1-1 strain.

A previously undescribed form of congenital disorder of glycosylation with variable presentation in siblings: Early fetal loss with hydrops fetalis, and infant death with hypoproteinemia

“…The two siblings reported by de Koning et al [1998], with CDG-Ik [Schwarz et al, 2004] had similarities to our two patients, including facial dysmorphism (hypertelorism, micrognathia), multiple joint contractures and a large anterior fontanelle. Differences included the presence of genital abnormalities, iris coloboma and dilated cardiomyopathy and the absence of cerebral abnormalities on neuroimaging.…”

Defining the Phenotype in Congenital Disorder of Glycosylation Due to ALG1 Mutations

“…Previously, 9 pediatric patients have been reported to have ALG1-CDG. [10][11][12][13] Three ALG1-CDG patients had a lethal form with severe multiorgan involvement, generalized edema, epilepsy, coagulation abnormalities, and death in the first months of life. 10,11 One patient died of respiratory insufficiency at age 4 years.…”

Physical Interactions among Human Glycosyltransferases Involved in Dolichol-Linked Oligosaccharide Biosynthesis

“…We previously identified the HMT-1 gene, orthologous to the yeast ALG1 (31), which encodes human MT-I (32). Since then, it has been demonstrated by several groups that dysfunction of HMT-1 results in CDG-Ik (33)(34)(35)(36). Of seven substitutional mutations reported to drastically decrease MT-I activity, S150R and G145D mutations are notable, because Ser 150 and Gly 145 residues of human MT-I are neither conserved nor located within a conserved domain.…”