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 intronicmutation (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).
Hennet, T, Wevers, RA, Burda, P, Berger, EG, Imbach, T, Aebi, M, Kuhnert, P
Schuman, HC, Matthijs, G, Vorster, BC, Mienie, LJ, Lippert, MM, Dercksen, M, Jaeken, J, Honey, EM, Crutchley, AC
Thomas, JA, Freeze, HH, Eklund, EA, Sun, L, Van Hove, JL
Schenk, B, Berger, EG, Schollen, E, Grünewald, S, Hennet, T, Imbach, T, de Klerk, JB, Burda, P, Aebi, M, Matthijs, G, Wevers, RA, Jaeken, J
Westphal, V, Schottstädt, C, Freeze, HH, Marquardt, T
dolichyl-phosphate-glucose-glycolipid alpha-glucosyltransferase activity of ALG6 mutants [endoplasmic reticulum membrane]
Loss of function of ALG6 mutants [endoplasmic reticulum membrane]
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