Alternative titles; symbols
HGNC Approved Gene Symbol: GYS1
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:48,968,130-48,993,309 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | Glycogen storage disease 0, muscle | 611556 | Autosomal recessive | 3 |
Glycogen is a high molecular mass polysaccharide that serves as a repository of glucose for use in times of metabolic need. Glycogen synthase (EC 2.4.1.11) catalyzes the addition of glucose monomers to the growing glycogen molecule through the formation of alpha-1,4-glycoside linkages (Pederson et al., 2004).
Browner et al. (1989) cloned and sequenced a cDNA for human muscle glycogen synthase. They found that it encodes a protein of 737 amino acids. Its primary structure is not related either to bacterial glycogen synthase or to any glycogen phosphorylase. They concluded that the glycogen synthase mRNA expressed in both fetal and adult heart and skeletal muscle tissue are the same, based on the size of mRNA species that were hybridized. Liver glycogen synthase is distinct (see GYS2, 138571).
By Southern blot analysis of somatic cell hybrid DNAs, Groop et al. (1993) determined that the GYS1 gene is located on chromosome 19. Lehto et al. (1993) regionalized the GYS gene to 19q13.3 by fluorescence in situ hybridization.
To examine whether defective muscle GYS1 expression is associated with impaired glycogen synthesis in type 2 diabetes (see 125853) and whether the defect is inherited or acquired, Huang et al. (2000) measured GYS1 gene expression and enzyme activity in muscle biopsies taken before and after an insulin clamp in 12 monozygotic twin pairs discordant for type 2 diabetes and in 12 matched control subjects. The effect of insulin on GYS1 fractional activity, when expressed as the increment over the basal values, was significantly impaired in diabetic, but not in nondiabetic, twins compared with that in control subjects. Insulin increased GYS1 mRNA expression in control subjects and in nondiabetic and diabetic twins. The effect of insulin on GYS1 expression was, however, significantly reduced in the diabetic (P less than 0.003), but not in the nondiabetic, twins, compared with that in control subjects. The postclamp GYS1 mRNA levels correlated strongly with the hemoglobin A1c levels (r = -0.61; P less than 0.001). The authors concluded that insulin stimulates GYS1 mRNA expression and that impaired stimulation of GYS1 gene expression by insulin in patients with type 2 diabetes is acquired and most likely is secondary to chronic hyperglycemia.
Kollberg et al. (2007) summarized the functions of muscle glycogen synthase and liver glycogen synthase, the key enzymes of glycogen synthesis, encoded by the GYS1 and GYS2 (138571) genes, respectively. The liver enzyme expression is restricted to the liver, whereas the muscle enzyme is ubiquitously expressed. Liver glycogen serves as a pool to maintain the blood glucose level during fasting, whereas muscle glycogen synthesis accounts for disposal of up to 90% of ingested glucose. The role of muscle and heart glycogen is to provide critical energy during bursts of activity and sustained muscle work. Deficiency of either muscle or liver glycogen synthase leads to distinct phenotypes; see 240600 for a description of liver glycogen synthase deficiency.
Muscle Glycogen Storage Disease
Kollberg et al. (2007) described 3 sibs with profound muscle and heart glycogen deficiency (GSD0B; 611556) caused by homozygosity for a stop codon mutation in the GYS1 gene (R462X; 138570.0001). Several findings in the patients were in accordance with the findings in muscle glycogen synthase knockout mice (Pederson et al. (2004, 2005, 2005)).
In an 8-year-old boy who died suddenly after exercise and in whom type 1 fiber predominance, lack of glycogen staining, and increased numbers of mitochondria (GSD0B; 611556) were observed at autopsy, Cameron et al. (2009) identified homozygosity for a 2-bp deletion in the GYS1 gene (138570.0002).
Polymorphic Alleles
Using a human complementary probe for glycogen synthase, the restriction enzyme XbaI, and Southern blot analysis, Groop et al. (1993) identified 2 polymorphic alleles, A1 and A2, in the GYS1 gene. The study was performed in Helsinki in Finnish patients. The A1A2 or A2A2 genotype was found in 30% of 107 patients with noninsulin-dependent diabetes mellitus (NIDDM; 125853) but in only 8% of 164 nondiabetic subjects without a family history of NIDDM (P less than 0.001). Diabetic patients with the A2 allele had a stronger family history of NIDDM (P = 0.019), a higher prevalence of hypertension (P = 0.008), and a more severe defect in insulin-stimulated glucose storage (P = 0.001) than the diabetic patients with the A1 allele. The concentration of the glycogen synthase protein in biopsy specimens of skeletal muscle from the patients with the A2 allele was normal, however, suggesting that expression of the gene was unaltered. The XbaI polymorphism was due to a change of a single base in an intron: the A2 allele had a substitution of thymidine for cytosine (CCTAGA to TCTAGA) 302 bp upstream from position 1970 of the cDNA. The storage of glucose as glycogen in skeletal muscle is frequently impaired in patients with NIDDM and their nondiabetic relatives. The association of the GYS1 polymorphism with diabetes could not be confirmed in France (Zouali et al., 1993) or Japan (Kadowaki et al., 1993).
In a genotype-discordant analysis of 122 sex-matched Finnish sib pairs from families with type 2 diabetes, Orho-Melander et al. (1999) found that sibs with the A2 variant of the XbaI polymorphism in the GYS1 gene had more hypertension, obesity, and microalbuminuria and were treated more often with insulin and antihypertensive medication than their sibs with the A1 variant. Diabetic A2 carriers had higher triglyceride and lower HDL cholesterol concentrations and an earlier age of onset of diabetes than diabetic sibs with the A1 variant. In nondiabetic sib pairs, the presence of the A2 variant was associated with higher diastolic blood pressure. Orho-Melander et al. (1999) replicated the association between the XbaI polymorphism and type 2 diabetes in 216 patients and 115 unrelated controls (p = 0.013).
Inbred mouse strains fed on a diabetogenic diet (high in fat and sucrose) differ in their propensities to develop features analogous to type 2 diabetes mellitus. To define chromosomal locations that control these characteristics, Seldin et al. (1994) studied recombinant inbred strains from diabetes-prone C57BL/6J and diabetes-resistant A/J strains. Hyperglycemia correlated with the marker D7Mit25 on mouse chromosome 7. This putative susceptibility locus is consistent with that of the glycogen synthase gene, which was implicated by Groop et al. (1993) in the pathogenesis of type 2 diabetes in the human. Seldin et al. (1994) found that fractional glycogen synthase activity in isolated muscle was significantly lower in normal B/6J diabetes-prone mice than in normal diabetes-resistant A/J mice, a finding similar to that reported in relatives of human patients with type 2 diabetes.
Pederson et al. (2004) found that 90% of Gys1 -/- mouse pups died without taking a breath due to failure of the lungs to inflate. Examination of Gys1 -/- embryos at 14.5 days postcoitum revealed venous and pulmonary congestion, severely hemorrhagic livers, and abnormal heart morphology, including thin ventricular walls resulting from decreased cell proliferation. Gys1 -/- mice that survived to adulthood had normal systolic blood pressure, heart rate, and electrocardiogram and no gross heart abnormalities, although there was a trend toward larger left ventricular mass, and the hearts of older males showed significant fibrosis. Biochemical analysis of skeletal muscle and heart of Gys1 -/- mice revealed the lack of glycogen; heterozygotes had glycogen levels that tended to be lower than those of wildtype mice.
Polysaccharide storage myopathy (PSSM) is a glycogenosis in horses characterized by abnormal glycogen accumulation in skeletal muscle and muscle damage with exertion. In PSSM-affected horses, McCue et al. (2008) identified a G-to-A change in exon 6 of the Gys1 gene, resulting in an arg309-to-his (R309H) substitution. R309 is conserved in human GYS1 and lies in a region that shares extensive identity with human GYS1. Functional analysis demonstrated elevated glycogen synthase activity in PSSM horses, indicating that R309H is a gain-of-function mutation.
In 3 sibs with muscle glycogen storage disease-0 (GSD0B; 611556), the offspring of consanguineous parents of Syrian origin, Kollberg et al. (2007) detected a 1384C-T transition in exon 11 of the GYS1 gene, which changed CGA, coding for arginine, to a TGA terminal signal. This premature stop codon was predicted to result in truncation of muscle glycogen synthase at amino acid residue 462 (R462X). Thus, the part of the enzyme harboring the active site was predicted to be lost. The mutation was found in heterozygosity in the unaffected parents and both paternal and maternal grandmothers, as well as in 1 of 100 ethnically matched controls.
In an 8-year-old boy with muscle glycogen storage disease-0 (GSD0B; 611556), Cameron et al. (2009) identified homozygosity for a 2-bp deletion (c.162_163delAG) in exon 2 of the GYS1 gene, causing a frameshift predicted to result in a premature termination codon and a 162-amino acid mutant protein rather than the full-length 737-amino acid protein. The unaffected parents and an unaffected sib were heterozygous for the mutation. Western blot analysis of patient fibroblasts confirmed complete loss of GYS protein, with no observable degradation products. In addition, patient fibroblasts showed reduced levels of glycogen synthase activity compared to controls.
Browner, M. F., Nakano, K., Bang, A. G., Fletterick, R. J. Human muscle glycogen synthase cDNA sequence: a negatively charged protein with an asymmetric charge distribution. Proc. Nat. Acad. Sci. 86: 1443-1447, 1989. [PubMed: 2493642] [Full Text: https://doi.org/10.1073/pnas.86.5.1443]
Cameron, J. M., Levandovskiy, V., MacKay, N., Utgikar, R., Ackerley, C., Chiasson, D., Halliday, W., Raiman, J., Robinson, B. H. Identification of a novel mutation in GYS1 (muscle-specific glycogen synthase) resulting in sudden cardiac that, that is diagnosable from skin fibroblasts. Molec. Genet. Metab. 98: 378-382, 2009. [PubMed: 19699667] [Full Text: https://doi.org/10.1016/j.ymgme.2009.07.012]
Groop, L. C., Kankuri, M., Schalin-Jantti, C., Ekstrand, A., Nikula-Ijas, P., Widen, E., Kuismanen, E., Eriksson, J., Franssila-Kallunki, A., Saloranta, C., Koskimies, S. Association between polymorphism of the glycogen synthase gene and non-insulin-dependent diabetes mellitus. New Eng. J. Med. 328: 10-14, 1993. Note: Erratum: New Eng. J. Med. 328: 1136 only, 1993. [PubMed: 8416266] [Full Text: https://doi.org/10.1056/NEJM199301073280102]
Huang, X., Vaag, A., Hansson, M., Weng, J., Laurila, E., Groop, L. Impaired insulin-stimulated expression of the glycogen synthase gene in skeletal muscle of type 2 diabetic patients is acquired rather than inherited. J. Clin. Endocr. Metab. 85: 1584-1590, 2000. [PubMed: 10770201] [Full Text: https://doi.org/10.1210/jcem.85.4.6535]
Kadowaki, T., Kadowaki, H., Yazaki, Y. Polymorphism of the glycogen synthase gene and non-insulin-dependent diabetes mellitus. (Letter) New Eng. J. Med. 328: 1569, 1993.
Kollberg, G., Tulinius, M., Gilljam, T., Ostman-Smith, I., Forsander, G., Jotorp, P., Oldfors, A., Holme, E. Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0. New Eng. J. Med. 357: 1507-1514, 2007. [PubMed: 17928598] [Full Text: https://doi.org/10.1056/NEJMoa066691]
Lehto, M., Stoffel, M., Groop, L., Espinosa, R., III, Le Beau, M. M., Bell, G. I. Assignment of the gene encoding glycogen synthase (GYS) to human chromosome 19, band q13.3. Genomics 15: 460-461, 1993. [PubMed: 8449521] [Full Text: https://doi.org/10.1006/geno.1993.1092]
McCue, M. E., Valberg, S. J., Miller, M. B., Wade, C., DiMauro, S., Akman, H. O., Mickelson, J. R. Glycogen synthase (GYS1) mutation causes a novel skeletal muscle glycogenosis. Genomics 91: 458-466, 2008. [PubMed: 18358695] [Full Text: https://doi.org/10.1016/j.ygeno.2008.01.011]
Orho-Melander, M., Almgren, P., Kanninen, T., Forsblom, C., Groop, L. C. A paired-sibling analysis of the XbaI polymorphism in the muscle glycogen synthase gene. Diabetologia 42: 1138-1145, 1999. [PubMed: 10447527] [Full Text: https://doi.org/10.1007/s001250051282]
Pederson, B. A., Chen, H., Schroeder, J. M., Shou, W., DePaoli-Roach, A. A., Roach, P. J. Abnormal cardiac development in the absence of heart glycogen. Molec. Cell. Biol. 24: 7179-7187, 2004. [PubMed: 15282316] [Full Text: https://doi.org/10.1128/MCB.24.16.7179-7187.2004]
Pederson, B. A., Cope, C. R., Schroeder, J. M., Smith, M. W., Irimia, J. M., Thurberg, B. L., DePaoli-Roach, A. A., Roach, P. J. Exercise capacity of mice genetically lacking muscle glycogen synthase: in mice, muscle glycogen is not essential for exercise. J. Biol. Chem. 280: 17260-17265, 2005. [PubMed: 15711014] [Full Text: https://doi.org/10.1074/jbc.M410448200]
Pederson, B. A., Schroeder, J. M., Parker, G. E., Smith, M. W., DePaoli-Roach, A. A., Roach, P. J. Glucose metabolism in mice lacking muscle glycogen synthase. Diabetes 54: 3466-3473, 2005. [PubMed: 16306363] [Full Text: https://doi.org/10.2337/diabetes.54.12.3466]
Seldin, M. F., Mott, D., Bhat, D., Petro, A., Kuhn, C. M., Kingsmore, S. F., Bogardus, C., Opara, E., Feinglos, M. N., Surwit, R. S. Glycogen synthase: a putative locus for diet-induced hyperglycemia. J. Clin. Invest. 94: 269-276, 1994. [PubMed: 8040269] [Full Text: https://doi.org/10.1172/JCI117317]
Zouali, H., Velho, G., Froguel, P. Polymorphism of the glycogen synthase gene and non-insulin-dependent diabetes mellitus. (Letter) New Eng. J. Med. 328: 1568, 1993. [PubMed: 8479502] [Full Text: https://doi.org/10.1056/NEJM199305273282113]