Alternative titles; symbols
HGNC Approved Gene Symbol: ALG2
SNOMEDCT: 897592003;
Cytogenetic location: 9q22.33 Genomic coordinates (GRCh38) : 9:99,216,425-99,221,942 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q22.33 | Congenital disorder of glycosylation, type Ii | 607906 | Autosomal recessive | 3 |
| Myasthenic syndrome, congenital, 14, with tubular aggregates | 616228 | Autosomal recessive | 3 |
The ALG2 gene encodes an alpha-1,3-mannosyltransferase that catalyzes the second and third mannosylation steps in the N-linked glycosylation pathway (summary by Cossins et al., 2013).
By searching databases for homologs of yeast Alg2, Thiel et al. (2003) identified human ALG2. The predicted 416-amino acid ALG2 protein shares 37% identity with yeast Alg2.
In mouse skeletal muscle, Cossins et al. (2013) found expression of the Alg2 gene at the endplate region of the neuromuscular junction, where it colocalized with alpha-bungarotoxin, consistent with localization at the acetylcholine receptor (AChR).
By genomic sequence analysis, Thiel et al. (2003) mapped the ALG2 gene to chromosome 9q22.
Congenital Disorder of Glycosylation Ii
Thiel et al. (2003) reported a patient with a molecular defect in glycoprotein biosynthesis that affects, at the cytosolic side of the endoplasmic reticulum (ER), the transfer of mannosyl residues from GDP-Man to Man(1)GlcNAc(2)-PP-dolichol by the enzyme ALG2. They designated this disorder congenital disorder of glycosylation (CDG) Ii (607906). In this patient, Thiel et al. (2003) identified compound heterozygous mutations in the ALG2 gene: a 1-bp deletion (607905.0001) and a 1-bp substitution (607905.0002). Expression of wildtype but not of mutant ALG2 cDNA restored the mannosyltransferase activity and the biosynthesis of dolichol-linked oligosaccharides both in patient fibroblasts and in yeast cells with an Alg2 mutation.
In 3 patients, including a sib pair, from unrelated Argentinian families with CDG Ii, Papazoglu et al. (2021) identified a homozygous missense mutation in the ALG2 gene (R251L; 607905.0005). The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in both sets of parents. All 3 patients had abnormal serum transferrin N-glycans and abnormal total serum glycoprotein N-glycans on mass spectrometry analysis, with an overall pattern suggesting serum N-glycan accumulation of high mannosylated glycoforms as a potential diagnostic pattern in patients with CDG Ii.
Congenital Myasthenic Syndrome 14
In 4 sibs, born of consanguineous Saudi Arabian parents, with congenital myasthenic syndrome-14 (CMS14; 616228), Cossins et al. (2013) identified a homozygous ins/del mutation in the ALG2 gene (607905.0003). The mutation was found by a combination of linkage analysis and exome sequencing and segregated with the disorder in the family. An unrelated patient born of consanguineous Italian patients with a similar disorder was homozygous for a missense mutation in the ALG2 gene (V68G; 607905.0004); the mutation was found by whole-genome sequencing.
In 3 patients from a large consanguineous Saudi Arabian Bedouin family with CMS14, Monies et al. (2014) identified the same homozygous ins/del mutation in exon 1 of the ALG2 gene as that found by Cossins et al. (2013).
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human ALG2 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a patient with congenital disorder of glycosylation type Ii (CDG1I; 607906), Thiel et al. (2003) identified compound heterozygosity for 2 mutations in the ALG2 gene. One mutation was a 1-bp deletion (G) at nucleotide 1040, and the other was a G-to-T transversion at nucleotide 393 (607905.0002). The deletion of 1040G caused a frameshift that altered the sequence after amino acid 346 and led to a premature translation stop at amino acid 372. At the level of RNA, the patient was homozygous for this mutation, indicating that the transcript carrying the 393G-T substitution was unstable. The patient's mother was heterozygous for the 1040G deletion. The father was heterozygous for the 393G-T substitution, and no transcripts with the 393G-T substitution were detected in him.
For discussion of the c.393G-T mutation in the ALG2 gene that was found in compound heterozygous state in a patient with CDG1I (607906) by Thiel et al. (2003), see 607905.0001.
In 4 sibs, born of consanguineous Saudi Arabian parents, with congenital myasthenic syndrome-14 (CMS14; 616228), Cossins et al. (2013) identified a homozygous indel mutation in exon 1 of the ALG2 gene (c.214_226del/ins), resulting in the replacement of several conserved residues in the glycosyltransferase-4-like domain (p.72_75delGDWLinsSPR). The inserted snippet is the reverse complement of the sequence spanning the mutant locus, but is displaced by 2 nucleotides upstream. The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 132), 1000 Genomes Project, or Exome Variant Server databases, or in 96 in-house control exomes.
In 3 patients from a large consanguineous Saudi Arabian Bedouin family with CMS14, Monies et al. (2014) identified the same homozygous del/ins mutation in exon 1 of the ALG2 gene as that found by Cossins et al. (2013). Monies et al. (2014) reported the numbering as c.214_224del. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. The families reported by Monies et al. (2014) and Cossins et al. (2013) both originated from the same small village, suggesting a common founder.
In an man, born of consanguineous Italian parents, with congenital myasthenic syndrome-14 (CMS14; 616228), Cossins et al. (2013) identified a homozygous c.203T-G transversion in exon 1 of the ALG2 gene, resulting in a val68-to-gly (V68G) substitution at a conserved residue. Val68 was predicted to localize to the endoplasmic reticulum lumen, and the variant was considered unlikely to affect the catalytic activity of the enzyme. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases. Western blot analysis of patient skeletal muscle and HEK293 cells transfected with the mutation showed severely reduced expression of the mutant protein, about 20% of controls.
In 3 patients, including a sib pair, from 2 unrelated Argentinian families with congenital disorder of glycosylation type Ii (CDG1I; 607906), Papazoglu et al. (2021) identified homozygosity for a c.752G-T transversion in the ALG2 gene, resulting in an arg251-to-leu (R251L) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in both sets of parents. All 3 patients had abnormal serum transferrin N-glycans and abnormal total serum glycoprotein N-glycans on mass spectrometry analysis. Clinical features in all 3 patients included seizures and developmental delay.
Cossins, J., Belaya, K., Hicks, D., Salih, M. A., Finlayson, S., Carboni, N., Liu, W. W., Maxwell, S., Zoltowska, K., Farsani, G. T., Laval, S., Seidhamed, M. Z., WGS500 Consortium, Donnelly, P., Bentley, D., McGowan, S. J., Muller, J., Palace, J., Lochmuller, H., Beeson, D. Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain 136: 944-956, 2013. [PubMed: 23404334] [Full Text: https://doi.org/10.1093/brain/awt010]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Monies, D. M., Al-Hindi, H. N., Al-Muhaizea, M. A., Jaroudi, D. J., Al-Younes, B., Naim, E. A., Wakil, S. M., Meyer, B. F., Bohlega, S. Clinical and pathological heterogeneity of a congenital disorder of glycosylation manifesting as a myasthenic/myopathic syndrome. Neuromusc. Disord. 24: 353-359, 2014. [PubMed: 24461433] [Full Text: https://doi.org/10.1016/j.nmd.2013.12.010]
Papazoglu, G. M., Cubilla, M., Pereyra, M., de Kremer, R. D., Perez, B., Sturiale, L., Asteggiano, C. G. Mass spectometry glycophenotype characterization of ALG2-CDG in Argentinean patients with a new genetic variant in homozygosis. Glycoconj. J. 38: 191-200, 2021. [PubMed: 33644825] [Full Text: https://doi.org/10.1007/s10719-021-09976-w]
Thiel, C., Schwarz, M., Peng, J., Grzmil, M., Hasilik, M., Braulke, T., Kohlschutter, A., von Figura, K., Lehle, L., Korner, C. A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis. J. Biol. Chem. 278: 22498-22505, 2003. [PubMed: 12684507] [Full Text: https://doi.org/10.1074/jbc.M302850200]