Alternative titles; symbols
HGNC Approved Gene Symbol: ALG1
SNOMEDCT: 720941007;
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:5,071,843-5,087,379 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Congenital disorder of glycosylation, type Ik | 608540 | Autosomal recessive | 3 |
The biosynthesis of lipid-linked oligosaccharides is highly conserved among eukaryotes and is catalyzed by 14 glycosyltransferases in an ordered stepwise manner. Mannosyltransferase I (MT I) catalyzes the first mannosylation step in this process.
By EST database searching with the S. cerevisiae MT I gene (ALG1) and subsequent screening of a human fetal brain cDNA library, Takahashi et al. (2000) isolated a cDNA corresponding to the human homolog, which they called HMAT1. HMAT1 encodes a 464-amino acid protein that shares 36% amino acid identity with the S. cerevisiae and C. elegans gene products. HMAT1 contains a hydrophobic region at the N terminus followed by short hydrophilic and hydrophobic regions. Takahashi et al. (2000) demonstrated that HMAT1 complemented the temperature-sensitive phenotype of a yeast strain lacking functional MT I due to an ALG1 mutation, indicating that the function of this enzyme is conserved between yeast and human.
Scott (2000) mapped the HMAT1 gene to chromosome 16p13.3 based on sequence similarity between the MT1 sequence (GenBank AB019038) and a chromosome 16 clone (GenBank AC007011).
In patients with congenital disorder of glycosylation type Ik (608540), Schwarz et al. (2004) and Kranz et al. (2004) identified mutations in the ALG1 gene (605907.0001-605907.0002).
Grubenmann et al. (2004) used a fluorescent method to detect accumulation of dolichylpyrophosphate-GlcNAc2 in a previously untyped CDG patient. The accumulation pattern suggested a deficiency of the ALG1 beta-1,4 mannosyltransferase. Sequence analysis identified compound heterozygosity for 2 mutations in the ALG1 gene (see 605907.0003).
In 5 unrelated French patients with CDG type Ik, Dupre et al. (2010) identified homozygous or compound heterozygous mutations in the ALG1 gene, including 7 novel mutations (see, e.g., 605907.0004-605907.0007). The phenotype was severe, with neurologic impairment in all patients and dysmorphic features in 4.
In a patient with CDG Ik and nephrotic syndrome, Harshman et al. (2016) identified homozygosity for the previously identified S258L mutation in the ALG1 gene (605907.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
In a patient with congenital disorder of glycosylation type Ik (CDG1K; 608540), Schwarz et al. (2004) identified a homozygous 773C-T transition in exon 7 of the ALG1 gene, resulting in a ser258-to-leu (S258L) substitution. Both parents were heterozygous for the mutation.
In a patient with CDG Ik, Kranz et al. (2004) identified homozygosity for the S258L mutation.
In a patient with CDG Ik and nephrotic syndrome, Harshman et al. (2016) identified homozygosity for the S258L mutation.
In a patient with congenital disorder of glycosylation type Ik (CDG1K; 608540), Kranz et al. (2004) identified compound heterozygosity for mutations in the ALG1 gene: a 1025A-C transversion, resulting in a glu342-to-pro (E342P) substitution, and S258L (605907.0001).
In a patient with congenital disorder of glycosylation type Ik (CDG1K; 608540), Grubenmann et al. (2004) identified compound heterozygosity for mutations in the ALG1 gene: a 450C-G transversion in exon 4, resulting in a ser150-to-arg (S150R) substitution, and S258L (605907.0001).
In a patient with congenital disorder of glycosylation type Ik (CDG1K; 608540), Dupre et al. (2010) identified a homozygous 1129A-G transition in exon 11 of the ALG1 gene, resulting in a met377-to-val (M377V) substitution in a conserved residue. The mutation was not found in 164 control alleles. Detailed biochemical studies in patient cell lines showed an accumulation of the second intermediate in the biosynthesis of LLO, GlcNAc2-PP-dolichol, as well as a selective defect of MT1 activity (less than 10% of wildtype). The phenotype was severe, with neurologic impairment and dysmorphic features.
In a patient with congenital disorder of glycosylation type Ik (CDG1K; 608540), Dupre et al. (2010) identified compound heterozygosity for 2 mutations in the ALG1 gene: a 434G-A transition in exon 4, resulting in a gly145-to-asp (G145D) substitution, and S258L (605907.0001). Neither mutation was found in 164 control alleles. Detailed biochemical studies in patient cell lines showed an accumulation of the second intermediate in the biosynthesis of LLO, GlcNAc2-PP-dolichol, as well as a selective defect of MT1 activity (less than 10% of wildtype). The phenotype was severe, with neurologic impairment and dysmorphic features.
In a patient with congenital disorder of glycosylation type Ik (CDG1K; 608540), Dupre et al. (2010) identified compound heterozygosity for 2 mutations in the ALG1 gene: a 1263G-A transition in exon 12, resulting in a cys396-to-ter (C396X) substitution, and an 826C-T transition in exon 7, resulting in an arg276-to-trp (R276W; 605907.0007) substitution. The mutations were not found in 164 control alleles. Detailed biochemical studies in patient cell lines showed an accumulation of the second intermediate in the biosynthesis of LLO, GlcNAc2-PP-dolichol, as well as a selective defect of MT1 activity (less than 10% of wildtype). The phenotype was severe, with neurologic impairment and dysmorphic features.
For discussion of the arg276-to-trp (R276W) mutation in the ALG1 gene that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type Ik (CDG1K; 608540) by Dupre et al. (2010), see 605907.0006.
Dupre, T., Vuillaumier-Barrot, S., Chantret, I., Sadou Yaye, H., Le Bizec, C., Afenjar, A., Altuzarra, C., Barnerias, C., Burglen, L., de Lonlay, P., Feillet, F., Napuri, S., Seta, N., Moore, S. E. H. Guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferase deficiency (congenital disorders of glycosylation type Ik): five new patients and seven novel mutations. J. Med. Genet. 47: 729-735, 2010. Note: Erratum: J. Med. Genet. 52: 216 only, 2015. [PubMed: 20679665] [Full Text: https://doi.org/10.1136/jmg.2009.072504]
Grubenmann, C. E., Frank, C. G., Hulsmeier, A. J., Schollen, E., Matthijs, G., Mayatepek, E., Berger, E. G., Aebi, M., Hennet, T. Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik. Hum. Molec. Genet. 13: 535-542, 2004. [PubMed: 14709599] [Full Text: https://doi.org/10.1093/hmg/ddh050]
Harshman, L. A., Ng, B. G., Freeze, H. H., Trapane, P., Dolezal, A., Brophy, P. D., Brumbaugh, J. E. Congenital nephrotic syndrome in an infant with ALG1-congenital disorder of glycosylation. Pediat. Int. 58: 785-788, 2016. [PubMed: 27325525] [Full Text: https://doi.org/10.1111/ped.12988]
Kranz, C., Denecke, J., Lehle, L., Sohlbach, K., Jeske, S., Meinhardt, F., Rossi, R., Gudowius, S., Marquardt, T. Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I. Am. J. Hum. Genet. 74: 545-551, 2004. [PubMed: 14973782] [Full Text: https://doi.org/10.1086/382493]
Schwarz, M., Thiel, C., Lubbehusen, J., Dorland, B., de Koning, T., von Figura, K., Lehle, L., Korner, C. Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik. Am. J. Hum. Genet. 74: 472-481, 2004. [PubMed: 14973778] [Full Text: https://doi.org/10.1086/382492]
Scott, A. Personal Communication. Baltimore, Md. 8/8/2000.
Takahashi, T., Honda, R., Nishikawa, Y. Cloning of the human cDNA which can complement the defect of the yeast mannosyltransferase I-deficient mutant alg 1. Glycobiology 10: 321-327, 2000. [PubMed: 10704531] [Full Text: https://doi.org/10.1093/glycob/10.3.321]