Gene map locus
1p22.3TEXT
DESCRIPTION
The ALG6 gene encodes Man(9)GlcNAc(2)-PP-Dol alpha-1,3-glucosyltransferase.
CLONING
Using degenerate PCR within regions of yeast ALG6 that are dissimilar to the closely related yeast ALG8 (608103) to screen a human T-cell cDNA library, Imbach et al. (1999) obtained a complete cDNA encoding the ortholog of S. cerevisiae ALG6. Human ALG6 encodes a 507-amino acid transmembrane protein that is 51% similar to the yeast protein. Northern blot analysis revealed expression of a 2.4-kb ALG6 transcript in pancreas, placenta, liver, heart, brain, kidney, skeletal muscle, and lung. 
GENE STRUCTURE
Imbach et al. (2000) determined that the ALG6 gene contains 14 exons and spans approximately 55 kb.
MAPPING
By screening an EST database for fragments identical to ALG6, Imbach et al. (2000) mapped the ALG6 gene to chromosome 1p22.3.
MOLECULAR GENETICS
Congenital disorder of glycosylation type Ic (CDG Ic, CDG1C; 603147) is characterized by an accumulation of dolichyl pyrophosphate-linked Man(9)GlcNAc(2) within the cells of affected patients. In 4 patients CDG1C reported by Burda et al. (1998), Imbach et al. (1999) identified the same homozygous mutation (A333V; 604566.0001) in the ALG6 gene. ALG6-deficient yeast strains have compromised hypoglycosylation of proteins because the nonglucosylated precursor is inefficiently transferred to protein. Expression of the normal human allele of ALG6 rescues defective glycosylation in ALG6-deficient yeast. By contrast, the A333V mutant protein was incapable of rescuing the impaired glycosylation in yeast.
Imbach et al. (2000) identified 7 additional cases of CDG1C among a group of 35 CDG patients by PCR amplification and sequencing of ALG6 exons in fibroblast cell lines. Four patients were homozygous for the A333V mutation and haplotype analysis suggested a founder effect. Another individual was compound heterozygous for the A333V mutation and a splice site mutation (604566.0003), and a pair of affected sibs was homozygous for missense mutation (604566.0002).
Westphal et al. (2000) identified compound heterozygosity for 2 pathogenic mutations in the ALG6 gene (604566.0003 and 604566.0004) in a patient with CDG1C.
Although a 911T-C transition, resulting in an F304S substitution, was described in relation to CDG Ic by Imbach et al. (2000), Westphal et al. (2000), and Hanefeld et al. (2000), Vuillaumier-Barrot et al. (2001) identified the transition in healthy French individuals, confirming that it is a common polymorphism. They found 23 heterozygous (42.6%) and 3 homozygous (5.5%) individuals, yielding an allele frequency of 27% in the French population.
Among a total of 55 patients with CDG1A (212065), Westphal et al. (2002) found that the ALG6 F304S polymorphism was almost twice as frequent in severely affected patients (0.41) compared to moderate or mildly affected patients (0.21). Functional expression studies showed that the F304S allele had a reduced ability to rescue defective glycosylation of an ALG6-deficient strain of S. cerevisiae during rapid growth. Westphal et al. (2002) concluded that the presence of the F304S allele may act as a genetic modifier to exacerbate the clinical outcome in severely affected CDG1A patients.
.0001 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ic [ALG6, ALA333VAL]
In 4 unrelated patients with CDG Ic (603147), Imbach et al. (1999) identified a 998C-T transition that led to an ala333-to-val (A333V) amino acid substitution in the human homolog of the yeast ALG6 gene.
.0002 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ic [ALG6, SER478PRO ] 
In 2 sibs with CDG Ic (603147), Imbach et al. (2000) identified a homozygous 1432T-C transition in exon 14 of the ALG6 gene, resulting in a ser478-to-pro (S478P) substitution. Both patients also were homozygous for a 911T-C transition in exon 10, resulting in a phe304-to-ser (F304S) substitution. Transfection studies showed that the S478P mutant protein failed to restore the glycosylation defect in yeast, whereas the F304S mutant restored the glycosylation defect similar to that achieved by wildtype, suggesting it is a 'mild' mutation.
Vuillaumier-Barrot et al. (2001) identified the 911T-C transition in healthy French individuals and confirmed that it is a common polymorphism.
.0003 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ic [ALG6, IVS3DS, G-A, +5 ]
In a patient with CDG Ic (603147), Imbach et al. (2000) identified compound heterozygosity for 2 mutations in the ALG6 gene: a G-to-A transition in intron 3 and the common A333V mutation (604566.0001). The splice site mutation resulted in the skipping of exon 3 which encodes a conserved domain.
Westphal et al. (2000) identified the IVS3G-A+5 splice site mutation in compound heterozygosity with another pathogenic mutation (604566.0004) in a patient with CDG1C. The mutant protein lacked 30 amino acids including a potential glycosylation site. Functional expression studies showed that the mutant protein could not rescue the glycosylation defect in yeast.
.0004 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ic [ALG6, 3-BP DEL, 895ATA ]
In a patient with CDG Ic (603147), Westphal et al. (2000) identified compound heterozygosity for 2 pathogenic mutations in the ALG6 gene: a splice site mutation resulting in the skipping of exon 3 (604566.0003) inherited from the mother, and a 3-bp deletion (895delATA) resulting in deletion of ile299 within a transmembrane domain inherited from the father. The allele with the 3-bp deletion also carried an F304S polymorphism. Functional expression studies showed that although the paternal allele with the 3-bp deletion and F304S was able to almost completely rescue the glycosylation defect in yeast, it produced an inefficiently transcribed or unstable mRNA with reduced expression.
REFERENCES
- 1. Burda, P.; Borsig, L.; de Rijk-Andel, J.; Wevers, R.; Jaeken, J.; Carchon, H.; Berger, E. G.; Aebi, M. :
- A novel carbohydrate-deficient glycoprotein syndrome characterized by a deficiency in glucosylation of the dolichol-linked oligosaccharide. J. Clin. Invest. 102: 647-652, 1998.
PubMed ID : 9710431
- 2. Hanefeld, F.; Korner, C.; Holzbach-Eberle, U.; von Figura, K. :
- Congenital disorder of glycosylation-Ic: case report and genetic defect. Neuropediatrics 31: 60-62, 2000.
PubMed ID : 10832578
- 3. Imbach, T.; Burda, P.; Kuhnert, P.; Wevers, R. A.; Aebi, M.; Berger, E. G.; Hennet, T. :
- A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic. Proc. Nat. Acad. Sci. 96: 6982-6987, 1999.
PubMed ID : 10359825
- 4. Imbach, T.; Grunewald, S.; Schenk, B.; Burda, P.; Schollen, E.; Wevers, R. A.; Jaeken, J.; de Klerk, J. B. C.; Berger, E. G.; Matthijs, G.; Aebi, M.; Hennet, T. :
- Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic. Hum. Genet. 106: 538-545, 2000.
PubMed ID : 10914684
- 5. Vuillaumier-Barrot, S.; Le Bizec, C.; Durand, G.; Seta, N. :
- The T911C (F304S) substitution in the human ALG6 gene is a common polymorphism and not a causal mutation of CDG-Ic. J. Hum. Genet. 46: 547-548, 2001.
PubMed ID : 11558905
- 6. Westphal, V.; Kjaergaard, S.; Schollen, E.; Martens, K.; Grunewald, S.; Schwartz, M.; Matthijs, G.; Freeze, H. H. :
- A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency. Hum. Molec. Genet. 11: 599-604, 2002.
PubMed ID : 11875054
- 7. Westphal, V.; Schottstadt, C.; Marquardt, T.; Freeze, H. H. :
- Analysis of multiple mutations in the hALG6 gene in a patient with congenital disorder of glycosylation Ic. Molec. Genet. Metab. 70: 219-223, 2000.
CONTRIBUTORS
George E. Tiller - updated : 10/9/2002
Victor A. McKusick - updated : 10/11/2001
Paul J. Converse - updated : 9/18/2000
Victor A. McKusick - updated : 6/13/2000
CREATION DATE
Paul J. Converse : 2/18/2000
EDIT HISTORY
carol : 6/26/2007
ckniffin : 6/26/2007
ckniffin : 6/22/2007
ckniffin : 6/22/2007
cwells : 11/7/2003
mgross : 9/18/2003
cwells : 10/9/2002
mcapotos : 10/26/2001
mcapotos : 10/11/2001
mgross : 9/18/2000
mcapotos : 7/20/2000
mcapotos : 6/29/2000
terry : 6/13/2000
carol : 2/18/2000
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