Zusammenfassung
Deficiency of GDP- Man: Man(1)GlcNAc(2)- PP- dolichol mannosyltransferase ( hALG2), is the cause of a new type of congenital disorders of glycosylation ( CDG) designated CDG- Ii. The patient presented normal at birth but developed in the 1st year of life a multisystemic disorder with mental retardation, seizures, coloboma of the iris, hypomyelination, hepatomegaly, and coagulation abnormalities. ...
Zusammenfassung
Deficiency of GDP- Man: Man(1)GlcNAc(2)- PP- dolichol mannosyltransferase ( hALG2), is the cause of a new type of congenital disorders of glycosylation ( CDG) designated CDG- Ii. The patient presented normal at birth but developed in the 1st year of life a multisystemic disorder with mental retardation, seizures, coloboma of the iris, hypomyelination, hepatomegaly, and coagulation abnormalities. An accumulation of Man1GlcNAc2- PP- dolichol and Man(2)GlcNAc(2)- PP- dolichol was observed in skin fibroblasts of the patient. Incubation of patient fibroblast extracts with Man1GlcNAc2- PP- dolichol and GDP- mannose revealed a severely reduced activity of the mannosyltransferase elongating Man1GlcNAc2- PP dolichol. Because the Saccharomyces cerevisiae mutant alg2- 1 was known to accumulate the same shortened dolichol- linked oligosaccharides as the patient, the yeast ALG2 sequence was used to identify the human ortholog. Genetic analysis revealed that the patient was heterozygous for a single nucleotide deletion and a single nucleotide substitution in the human ortholog of yeast ALG2. Expression of wild type but not of mutant hALG2 cDNA restored the mannosyltransferase activity and the biosynthesis of dolichol-linked oligosaccharides both in patient fibroblasts and in the alg2- 1 yeast cells. hALG2 was shown to act as an alpha1,3- mannosyltransferase. The resulting Manalpha1,3-ManGlcNAc(2)- PP dolichol is further elongated by a yet unknown alpha 1,6- mannosyltransferase.
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