HGNC Approved Gene Symbol: GYG1
SNOMEDCT: 1228849007;
Cytogenetic location: 3q24 Genomic coordinates (GRCh38) : 3:148,991,540-149,031,775 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q24 | ?Glycogen storage disease XV | 613507 | Autosomal recessive | 3 |
| Polyglucosan body myopathy 2 | 616199 | Autosomal recessive | 3 |
The GYG1 gene encodes glycogenin-1, a glycosyltransferase (EC 2.4.1.186) that catalyzes 2 autoglucosylation reactions using UDP-glucose as the donor substrate during the initiation of glycogen synthesis. GYG1 is expressed in skeletal and heart muscle. During initiation, the covalent attachment of a glucose residue to glycogenin is followed by elongation to form an oligosaccharide chain (summary by Viskupic et al., 1992 and Nilsson et al., 2012).
Viskupic et al. (1992) isolated cDNAs encoding glycogenin from rabbit muscle, rat, and cow. Recombinant mammalian glycogenin was enzymatically active and capable of self-glucosylation. After incubation with UDP-glucose, the recombinant protein was able to serve as a substrate for glycogen synthase, leading to the production of high M(r) polysaccharide.
Barbetti et al. (1996) identified a human glycogenin cDNA. The predicted 333-amino acid human protein shares 93% identity with rabbit muscle glycogenin. Northern blot analysis revealed that the 2.4-kb glycogenin mRNA was expressed prominently in human skeletal muscle and heart, and to a lesser extent in several other tissues.
Imagawa et al. (2014) noted that GYG1 is not expressed in liver or brain, tissues in which GYG2 (300198) is highly expressed.
By FISH, Barbetti et al. (1996) mapped the GYG1 gene to chromosome 3q25.1. Using somatic cell hybrid analysis, they confirmed the chromosome 3 localization and also identified intronless glycogenin-related sequences on chromosomes 12 and 13. By FISH, Lomako et al. (1996) mapped the GYG1 gene to chromosome 3q24.
Glycogen Storage Disease XV
In a 27-year-old man with muscle weakness and cardiac arrhythmias associated with glycogen depletion, here designated glycogen storage disease XV (GSD15; 613507), Moslemi et al. (2010) identified compound heterozygosity for a nonsense (603942.0001) and a missense (603942.0002) mutation in the GYG1 gene. Western blotting demonstrated the presence of unglucosylated glycogenin-1 in the patient's skeletal and cardiac muscle.
Polyglucosan Body Myopathy 2
In 7 unrelated patients with polyglucosan body myopathy-2 (PGBM2; 616199), Malfatti et al. (2014) identified homozygous or compound heterozygous mutations in the GYG1 gene (see, e.g., 603942.0003-603942.0007). The most common mutation was a splice site mutation (603942.0003), found in the homozygous or compound heterozygous state in 4 patients. Segregation analysis of the mutations in families was not reported. Unlike the patient reported by Moslemi et al. (2010), none of the 7 patients with PGBM2 had evidence of cardiac involvement. Some patients had absence of GYG1 protein in skeletal muscle tissue, whereas others had reduced levels of the protein with some residual function. Analysis of glycogenin-1 in skeletal muscle of 1 patient who had a deletion of the C terminus of GYG1 (603942.0004) indicated that the protein was autoglucosylated, but that elongation of the glycogen polymer was impaired. These findings suggested that the C terminus of GYG1 is important for glycogen synthase (GYS1; 138570) activity.
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 GYG1 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a 27-year-old man with muscle weakness and cardiac arrhythmias associated with glycogen depletion (GSD15; 613507), Moslemi et al. (2010) identified compound heterozygosity for a 1-bp deletion (487delG) in exon 5 of the GYG1 gene, resulting in a frameshift and premature termination sequence at codon 167, and a 248C-T transition in exon 3 of the GYG1 gene, resulting in a thr83-to-met (T83M; 603942.0002) substitution at a highly conserved residue. The patient's unaffected mother was heterozygous for the deletion, and his unaffected father and 2 brothers were heterozygous for the missense mutation. Neither mutation was found in 200 control chromosomes of similar ancestry. Functional studies in Chinese hamster ovary (CHO) cells showed that recombinant wildtype glycogenin-1 was autoglucosylated, whereas recombinant T83M-mutant glycogenin-1 was not. RFLP analysis and sequencing demonstrated that the allele carrying the 487delG mutation was not expressed at the transcript level.
For discussion of the thr83-to-met (T83M) mutation in the GYG1 gene that was found in compound heterozygous state in a patient with glycogen storage disease XV (GSD15; 613507) by Moslemi et al. (2010), see 603942.0001.
In in vitro expression studies, Nilsson et al. (2012) demonstrated that the T83M mutant was incapable of autoglucosylation after addition of UDP-glucose. The mutant protein was unable to catalyze the initial glucose-O-tyrosine 195 linkage. However, T83M was glucosylated when coexpressed with the enzymatically active T195F variant. The findings explained why the patient reported by Moslemi et al. (2010) who only expressed the T83M mutation had glycogen depletion in skeletal muscle.
In 2 unrelated patients with onset of polyglucosan body myopathy-2 (PGBM2; 616199) in the first 2 decades of life, Malfatti et al. (2014) identified a homozygous G-to-C transversion (c.143+3G-C) in intron 2 of the GYG1 gene, resulting in aberrant splicing with the skipping of exon 2, a frameshift, and premature termination (Asp3GlufsTer4). Two additional unrelated patients with later onset of the disorder were found to be compound heterozygous for this splice site mutation and another pathogenic GYG1 mutation (see, e.g., R324X, 603942.0004).
In a woman with onset of polyglucosan body myopathy-2 (PGBM2; 616199) at age 49 years, Malfatti et al. (2014) identified compound heterozygous mutations in the GYG1 gene: a c.970C-T transition in exon 8, resulting in an arg324-to-ter (R324X) substitution, and a splice site mutation resulting in a truncated protein (Asp3GlufsTer4; 603942.0003).
In a man with onset of polyglucosan body myopathy-2 (PGBM2; 616199) at age 39 years, Malfatti et al. (2014) identified compound heterozygous mutations in the GYG1 gene: a c.304G-C transversion in exon 4, resulting in an asp102-to-his (D102H) substitution, and a c.749G-A transition in exon 6, resulting in a trp250-to-ter (W250X; 603942.0006) substitution.
For discussion of the trp250-to-ter (W250X) mutation in the GYG1 gene that was found in compound heterozygous state in a patient with polyglucosan body myopathy-2 (PGBM2; 616199) by Malfatti et al. (2014), see 603942.0005.
In a woman with onset of polyglucosan body myopathy-2 (PGBM2; 616199) at age 61 years, Malfatti et al. (2014) identified a homozygous 1-bp deletion (c.484delG) in exon 5 of the GYG1 gene, resulting in a frameshift and premature termination (Thr163AspfsTer5). Her muscle weakness was confined to the intrinsic hand muscles and fingers.
Barbetti, F., Rocchi, M., Bossolasco, M., Cordera, R., Sbraccia, P., Finelli, P., Consalez, G. G. The human skeletal muscle glycogenin gene: cDNA, tissue expression, and chromosomal localization. Biochem. Biophys. Res. Commun. 220: 72-77, 1996. [PubMed: 8602861] [Full Text: https://doi.org/10.1006/bbrc.1996.0359]
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]
Imagawa, E., Osaka, H., Yamashita, A., Shiina, M., Takahashi, E., Sugie, H., Nakashima, M., Tsurusaki, Y., Saitsu, H., Ogata, K., Matsumoto, N., Miyake, N. A hemizygous GYG2 mutation and Leigh syndrome: a possible link? Hum. Genet. 133: 225-234, 2014. [PubMed: 24100632] [Full Text: https://doi.org/10.1007/s00439-013-1372-6]
Lomako, J., Mazuruk, K., Lomako, W. M., Alonso, M. D., Whelan, W. J., Rodriguez, I. R. The human intron-containing gene for glycogenin maps to chromosome 3, band q24. Genomics 33: 519-522, 1996. [PubMed: 8661012] [Full Text: https://doi.org/10.1006/geno.1996.0228]
Malfatti, E., Nilsson, J., Hedberg-Oldfors, C., Hernandez-Lain, A., Michel, F., Dominguez-Gonzalez, C., Viennet, G., Akman, H. O., Kornblum, C., Van den Bergh, P., Romero, N. B., Engel, A. G., DiMauro, S., Oldfors, A. A new muscle glycogen storage disease associated with glycogenin-1 deficiency. Ann. Neurol. 76: 891-898, 2014. [PubMed: 25272951] [Full Text: https://doi.org/10.1002/ana.24284]
Moslemi, A.-R., Lindberg, C., Nilsson, J., Tajsharghi, H., Andersson, B., Oldfors, A. Glycogenin-1 deficiency and inactivated priming of glycogen synthesis. New Eng. J. Med. 362: 1203-1210, 2010. [PubMed: 20357282] [Full Text: https://doi.org/10.1056/NEJMoa0900661]
Nilsson, J., Halim, A., Moslemi, A.-R., Pedersen, A., Nilsson, J., Larson, G., Oldfors, A. Molecular pathogenesis of a new glycogenosis caused by a glycogenin-1 mutation. Biochim. Biophys. Acta 1822: 493-499, 2012. [PubMed: 22198226] [Full Text: https://doi.org/10.1016/j.bbadis.2011.11.017]
Viskupic, E., Cao, Y., Zhang, W., Cheng, C., DePaoli-Roach, A. A., Roach, P. J. Rabbit skeletal muscle glycogenin. Molecular cloning and production of fully functional protein in Escherichia coli. J. Biol. Chem. 267: 25759-25763, 1992. [PubMed: 1281472]