| *605907 | ||||||||||||||||||
| ALG1, YEAST, HOMOLOG OF; ALG1 | ||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||
| ASPARAGINE-LINKED GLYCOSYLATION 1 HOMOLOG BETA-1,4 MANNOSYLTRANSFERASE HMAT1 HMT1 | ||||||||||||||||||
| HGNC Approved Gene Symbol: ALG1 | ||||||||||||||||||
| Cytogenetic location: 16p13.3 Genomic coordinates (GRCh37): 16:5,121,809 - 5,137,379 (from NCBI) | ||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||
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| TEXT | ||||||||||||||||||
| Description | ||||||||||||||||||
| 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. | ||||||||||||||||||
| Cloning | ||||||||||||||||||
| 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. | ||||||||||||||||||
| Mapping | ||||||||||||||||||
| 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). | ||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||
| 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. | ||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||
| Table View | ||||||||||||||||||
| .0001 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ik | ||||||||||||||||||
| ALG1, SER258LEU [dbSNP:rs28939378] | ||||||||||||||||||
| 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. | ||||||||||||||||||
| .0002 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ik | ||||||||||||||||||
| ALG1, GLU342PRO | ||||||||||||||||||
| In a patient with congenital disorder of glycosylation type Ik (608540), Kranz et al. (2004) identified compound heterozygosity for a 1025A-C transversion in the ALG1 gene, resulting in a glu342-to-pro (E342P) substitution, and the S258L (605907.0001) mutation. | ||||||||||||||||||
| .0003 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ik | ||||||||||||||||||
| ALG1, SER150ARG [dbSNP:rs121908340] | ||||||||||||||||||
| In a patient with congenital disorder of glycosylation type Ik (608540), Grubenmann et al. (2004) identified compound heterozygosity for a 450C-G transversion in exon 4 of the ALG1 gene, resulting in a ser150-to-arg (S150R), and the S258L (605907.0001) mutation. | ||||||||||||||||||
| .0004 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ik | ||||||||||||||||||
| ALG1, MET377VAL | ||||||||||||||||||
| In a patient with congenital disorder of glycosylation type Ik (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. | ||||||||||||||||||
| .0005 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ik | ||||||||||||||||||
| ALG1, GLY145ASP | ||||||||||||||||||
| In a patient with congenital disorder of glycosylation type Ik (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. | ||||||||||||||||||
| .0006 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ik | ||||||||||||||||||
| ALG1, CYS396TER | ||||||||||||||||||
| In a patient with congenital disorder of glycosylation type Ik (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. | ||||||||||||||||||
| .0007 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ik | ||||||||||||||||||
| ALG1, ARG276TRP | ||||||||||||||||||
| See 605907.0006 and Dupre et al. (2010). | ||||||||||||||||||
| REFERENCES | ||||||||||||||||||
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