Alternative titles; symbols
HGNC Approved Gene Symbol: GYS2
Cytogenetic location: 12p12.1 Genomic coordinates (GRCh38): 12:21,532,577-21,604,847 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p12.1 | Glycogen storage disease 0, liver | 240600 | Autosomal recessive | 3 |
Glycogen synthase catalyzes the rate-limiting step in glycogen synthesis. Its activity is regulated by a complex phosphorylation-dephosphorylation mechanism and by allosteric stimulators and inhibitors. Two isozymes of synthase, a skeletal muscle type (GYS1; 138570) and a liver type (GYS2), have been identified in rabbit and rat tissues using specific polyclonal antibodies. The skeletal muscle type isozyme is present in several organs in addition to skeletal muscle; the liver isozyme has been identified only in liver. Westphal and Nuttall (1992) purified and characterized the human liver synthase isozyme. They also cloned and sequenced the gene from a human liver cDNA library.
Orho et al. (1998) determined that the GYS2 gene comprises 16 exons and spans more than 30 kb.
By using the entire cDNA coding sequence as a probe in fluorescence in situ hybridization, Nuttall et al. (1994) mapped the GYS2 gene to 12p12.2. Consistent with the mapping of GYS1 and GYS2 to separate chromosomes is the lack of sequence homology between them.
Liver glycogen storage disease type 0 (GSD0A; 240600), or liver glycogen synthase deficiency, is a rare form of fasting hypoglycemia presenting in infancy or early childhood and accompanied by high blood ketones and low alanine and lactate concentrations. Although feeding relieves symptoms, it often results in postprandial hyperglycemia and hyperlactatemia. The glycogen synthase activity is low or immeasurable in liver biopsies, whereas the liver glycogen content is only moderately decreased. To investigate whether mutations in the GYS2 gene are involved in GSD0, Orho et al. (1998) determined the exon-intron structure of the GYS2 gene and examined 9 affected children from 5 families for linkage of GSD0 to the GYS2 gene, using intragenic and flanking polymorphic markers. After linkage to the chromosomal region 12p12.2, where the GYS2 gene had been mapped, was established, they screened the coding regions, the exon-intron boundary regions, and part of the putative promoter of the GYS2 gene for mutations. Mutations were found in all affected children, demonstrating that GSD0 is caused by molecular defects in the GYS2 gene.
In a male child born to unrelated Turkish parents living in Austria, Orho et al. (1998) demonstrated that liver glycogen storage disease type 0 (GSD0A; 240600) was associated with homozygosity for a mutation causing a premature stop codon in exon 5 of the GYS2 gene: arg246-to-ter (CGA-to-TGA). Two of his unaffected brothers carried the arg246-to-ter mutation on 1 allele. The patient had been referred at the age of 4 because of short stature. Serum growth hormone concentration was subnormal. After an overnight fast, the blood glucose was abnormally low, whereas free fatty acids and beta-hydroxybutyrate concentrations were high. In relation to the hypoglycemia, plasma insulin levels were appropriately reduced. An oral glucose tolerance test provoked an excessive rise of blood glucose and lactate, whereas free fatty acids and beta-hydroxybutyrate were normal. At age 7, a liver biopsy showed low glycogen synthase activity with glycogen content in the low to normal range.
In a female child who presented at age 5 with fasting hypoglycemia and postprandial hyperglycemia, Orho et al. (1998) demonstrated that liver glycogen storage disease type 0 (GSD0A; 240600) was caused by compound heterozygosity for a mutation in the 5-prime donor splice site of intron 6 and a pro479-to-gln mutation (P479Q; 138571.0003) (CCA to CAA) in exon 12. The splice site mutation was inherited from the mother; although the father's DNA was not available for study, the P479Q mutation presumably came from him. Symptoms of hypoglycemia in the proposita were prevented by ingestion of cornstarch. Her mental development had been slow. Her mother also developed hypoglycemia during prolonged fasting. Two other affected children in this family were also compound heterozygotes for the 2 mutations.
For discussion of the pro479-to-gln (P479Q) mutation in the GYS2 gene that was found in compound heterozygous state in a patient with fasting hypoglycemia and postprandial hyperglycemia (see GSD0A, 240600) by Orho et al. (1998), see 138571.0002.
In a female child born to unrelated German parents, Orho et al. (1998) found that liver glycogen storage disease type 0 (GSD0A; 240600) was associated with compound heterozygosity for 2 missense mutations: ala339 to pro (GCT to CCT) in exon 7, inherited from the mother; and met491 to arg (M491R; 138571.0005) (ATG to AGG) in exon 12, inherited from the father. At age 3.5, the patient had been drowsy in the mornings, and occasionally vomited; her pediatrician discovered hypoglycemia and marked ketonuria. At age 4 she was suspected of having liver disease. Metabolic profiles were indicative of GSD0A. Glycogen content in the liver was low and glycogen synthase activity was virtually absent.
For discussion of the met491-to-arg (M491R) mutation in the GYS2 gene that was found in compound heterozygous state in a patient with liver glycogen storage disease type 0 (GSD0A; 240600) by Orho et al. (1998), see 138571.0004.
In 2 brothers born to unrelated German parents, Orho et al. (1998) demonstrated that liver glycogen storage disease type 0 (GSD0A; 240600) was caused by compound heterozygosity for 2 missense mutations: asn39 to ser (AAT to AGT) in exon 1 and ser483 to pro (S483P; 138571.0007) (TCC to CCC) in exon 12. The younger brother, at age 2, appeared tired in the mornings and uninterested in breakfast. He recovered after eating. When he was 3.5 years of age, his pediatrician diagnosed hypoglycemia and ketonuria. Metabolic profiles were indicative of GSD0A.
For discussion of the ser483-to-pro (S483P) mutation in the GYS2 gene that was found in compound heterozygous state in 2 brothers with liver glycogen storage disease type 0 (GSD0A; 240600) by Orho et al. (1998), see 138571.0006.
In a brother and sister with liver glycogen storage disease type 0 (GSD0A; 240600), born to unrelated British parents, Orho et al. (1998) demonstrated that 1 GYS2 allele, inherited from the mother, carried a his446-to-asp mutation (CAC to GAC) in exon 11. No mutation that could have been inherited from the father was found despite SSCP analysis and direct sequencing of all the exons and 450 bp of the 5-prime flanking region of the GYS2 gene. The sister in this case had been born in 1966 and the brother in 1964. The sister had been reported by Aynsley-Green et al. (1977, 1977). In infancy, when nighttime feedings were discontinued, early morning behavioral changes, drowsiness, and lack of attention were noted in the sister. Symptoms were relieved by food intake. At 7 years of age, she had occasional morning convulsions. Fasting hypoglycemia and ketonuria were discovered and glycogen synthase deficiency was diagnosed by liver biopsy. At age 29, the sister gave birth to a healthy child (Byrne et al., 1995). When the brother became old enough to go through the night without feeding, he became drowsy and unresponsive in the morning until the first meal. Symptoms ceased after 3 years of age. At age 13 he was examined together with his sister and the metabolic profiles resembled those of his sister, resulting in a diagnosis of GSD0.
Aynsley-Green, A., Williamson, D. H., Gitzelmann, R. Hepatic glycogen synthetase deficiency: definition of syndrome from metabolic and enzyme studies on a 9-year-old girl. Arch. Dis. Child. 52: 573-579, 1977. [PubMed: 141912] [Full Text: https://doi.org/10.1136/adc.52.7.573]
Aynsley-Green, A., Williamson, D. H., Gitzelmann, R. The dietary treatment of hepatic glycogen synthetase deficiency. Helv. Paediat. Acta 32: 71-75, 1977. [PubMed: 106027]
Byrne, B. M., Gillmer, M. D., Turner, R. C., Aynsley-Green, A. Glucose homeostasis in adulthood and in pregnancy in a patient with hepatic glycogen synthetase deficiency. Brit. J. Obstet. Gynaec. 102: 931-933, 1995. [PubMed: 8534634] [Full Text: https://doi.org/10.1111/j.1471-0528.1995.tb10886.x]
Nuttall, F. Q., Gannon, M. C., Kubic, V. L., Hoyt, K. J. The human liver glycogen synthase isozyme gene is located on the short arm of chromosome 12. Genomics 19: 404-405, 1994. [PubMed: 8188280] [Full Text: https://doi.org/10.1006/geno.1994.1086]
Orho, M., Bosshard, N. U., Buist, N. R. M., Gitzelmann, R., Aynsley-Green, A., Blumel, P., Gannon, M. C., Nuttall, F. Q., Groop, L. C. Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0. J. Clin. Invest. 102: 507-515, 1998. [PubMed: 9691087] [Full Text: https://doi.org/10.1172/JCI2890]
Westphal, S. A., Nuttall, F. Q. Comparative characterization of human and rat liver glycogen synthase. Arch. Biochem. Biophys. 292: 479-486, 1992. [PubMed: 1731614] [Full Text: https://doi.org/10.1016/0003-9861(92)90019-s]