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

Stable Identifier
Reaction [transition]
Homo sapiens
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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
10359825 A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic

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

Proc Natl Acad Sci U S A 1999
23430515 ALG6-CDG in South Africa: Genotype-Phenotype Description of Five Novel Patients

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

JIMD Rep 2013
16007612 Clinical and molecular characterization of the first adult congenital disorder of glycosylation (CDG) type Ic patient

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

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

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

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, Freeze, HH, Marquardt, T

Mol. Genet. Metab. 2000
Catalyst Activity

dolichyl-phosphate-glucose-glycolipid alpha-glucosyltransferase activity of ALG6 mutants [endoplasmic reticulum membrane]

Normal reaction
Functional status

Loss of function of ALG6 mutants [endoplasmic reticulum membrane]

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