Defective DPM3 does not transfer mannose to DOLP to form DOLPman

Stable Identifier
R-HSA-4719354
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Dolichyl-phosphate mannosyltransferase (DPM), a heterotrimeric protein embedded in the endoplasmic reticulum membrane, mediates the transfer of mannose (from cytosolic GDP-mannose) to dolichyl phosphate (DOLP) to form dolichyl-phosphate-mannose (DOLPman). The first subunit of the heterotrimer (DPM1) appears to be the actual catalyst, and the other two subunits (DPM2 and 3) appear to stabilise it (Maeda et al. 2000). Defects in DPM3 can cause congenital disorder of glycosylation 1o (DPM3-CDG, CDG1o; MIM:612937), a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterised by under-glycosylated serum glycoproteins. CDG type 1 diseases result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency (Lefeber et al. 2009). Normally, the DPM3 subunit tethers the catalytic DPM1 subunit to the ER membrane. A homozygous 254T-C transition in the DPM3 gene results in a leu85-to-ser (L85S) substitution in a highly conserved residue in the coiled-coil domain. This mutant shows a reduced binding capacity to DPM1 which vastly reduces dolichyl-phosphate mannosyltransferase activity and therefore little or no DOLPman is formed (Lefeber et al. 2009).

Literature References
PubMed ID Title Journal Year
10835346 Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3

Maeda, Y, Tanaka, S, Hino, J, Kangawa, K, Kinoshita, T

EMBO J 2000
19576565 Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies

Lefeber, DJ, Sch├Ânberger, J, Morava, E, Guillard, M, Huyben, KM, Verrijp, K, Grafakou, O, Evangeliou, A, Preijers, FW, Manta, P, Yildiz, J, Gr├╝newald, S, Spilioti, M, van den Elzen, C, Klein, D, Hess, D, Ashida, H, Hofsteenge, J, Maeda, Y, Van den Heuvel, L, Lammens, M, Lehle, L, Wevers, RA

Am. J. Hum. Genet. 2009
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
dolichyl-phosphate beta-D-mannosyltransferase activity of DPM1:DPM2:DPM3 L85S [endoplasmic reticulum membrane]
Physical Entity
Activity
Normal reaction
Disease
Name Identifier Synonyms
congenital disorder of glycosylation type I 0050570
Authored
Reviewed
Created
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