Defective ALG6 does not add glucose to the N-glycan precursor

Stable Identifier
R-HSA-4724291
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6) normally adds the first glucose moiety to the lipid-linked oligosaccharide precursor (LLO aka N-glycan precursor) which is required for subsequent N-glycosylation of proteins (Imbach et al. 1999). Defects in ALG6 can cause congenital disorder of glycosylation 1c (ALG6-CDG, CDG-1c; MIM:603147), a multisystem disorder characterised by under-glycosylated serum glycoproteins (Imbach et al. 1999, Imbach et al. 2000, Westphal et al. 2000, Sun et al. 2005). ALG6 deficiency is accompanied by an accumulation of the N-glycan precursor (GlcNAc)2 (Man)9 (PP-Dol)1 (Imbach et al. 1999). 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. Mutations that can cause ALG6-CDG are A333V and S478P. The A333V mutation is the most commom mutation seen in ALG6-CDG patients. These mutations result in altered activity of ALG6 but don't completely abolish its activity (Imbach et al. 1999, Imbach et al. 2000, Dercksen et al. 2013). A c.257+5G>A splice site mutation (not shown here) that causes exon 3 skipping leads to a nonfunctional protein (Imbach et al. 2000, Westphal et al. 2000). Two more mutations can cause the build up of the N-glycan precursor (GlcNAc)2 (Man)9 (PP-Dol)1; a three bp deletion (897-899delAAT) in exon 9 and an intronic
mutation (680+2T>G) in intron 7 (neither shown here). Transduction of patient fibroblasts with a lentivirus carrying wildtype hALG6 improved the biochemical phenotype of the cells, confirming that these two mutations are disease-causing (Sun et al. 2005).

Literature References
PubMed ID Title Journal Year
23430515 ALG6-CDG in South Africa: Genotype-Phenotype Description of Five Novel Patients

Dercksen, M, Crutchley, AC, Honey, EM, Lippert, MM, Matthijs, G, Mienie, LJ, Schuman, HC, Vorster, BC, Jaeken, J

JIMD Rep 2013
10359825 A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic

Imbach, T, Burda, P, Kuhnert, P, Wevers, RA, Aebi, M, Berger, EG, Hennet, T

Proc Natl Acad Sci U S A 1999
16007612 Clinical and molecular characterization of the first adult congenital disorder of glycosylation (CDG) type Ic patient

Sun, L, Eklund, EA, Van Hove, JL, Freeze, HH, Thomas, JA

Am J Med Genet A 2005
10914684 Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic

Imbach, T, Gr├╝newald, S, Schenk, B, Burda, P, Schollen, E, Wevers, RA, Jaeken, J, de Klerk, JB, Berger, EG, Matthijs, G, Aebi, M, Hennet, T

Hum. Genet. 2000
10924277 Analysis of multiple mutations in the hALG6 gene in a patient with congenital disorder of glycosylation Ic

Westphal, V, Schottst├Ądt, C, Marquardt, T, Freeze, HH

Mol. Genet. Metab. 2000
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
dolichyl-phosphate-glucose-glycolipid alpha-glucosyltransferase activity of ALG6 mutants [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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