Alternative titles; symbols
HGNC Approved Gene Symbol: AGL
Cytogenetic location: 1p21.2 Genomic coordinates (GRCh38): 1:99,849,258-99,924,023 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p21.2 | Glycogen storage disease IIIa | 232400 | Autosomal recessive | 3 |
| Glycogen storage disease IIIb | 232400 | Autosomal recessive | 3 |
The AGL gene encodes the glycogen debrancher enzyme, a large monomeric protein with a molecular mass of approximately 160 kD. The enzyme has 2 catalytic activities: amylo-1,6-glucosidase (EC 3.2.1.33) and 4-alpha-glucanotransferase (EC 2.4.1.25). The 2 activities are determined at separate catalytic sites on the polypeptide chain and can function independently of each other. Both activities and glycogen binding are required for complete function (Shen et al., 1996; Endo et al., 2006).
Yang et al. (1992, 1992) isolated a full-length cDNA corresponding to the human muscle glycogen debranching enzyme. The deduced 1,532-residue protein has a molecular mass of approximately 173 kD. Northern blot analysis detected a 7-kb mRNA transcript. The liver mRNA sequence is identical to the muscle sequence for most of the length, except for the 5-prime end in which the liver sequence diverges completely from the muscle sequence, beginning with the putative transcription initiation site to the ninth nucleotide upstream of the translation initiation codon. Thus, the muscle and liver isoforms are generated via differential RNA transcription, with an alternative first exon usage, from a single gene. Shen et al. (1997) cited their unpublished data indicating that 17 additional amino acids precede the N terminus of the AGL gene sequence published by Yang et al. (1992).
Bao et al. (1996) stated that there are at least 6 isoforms of AGL produced by alternative splicing. The major isoform, isoform 1, begins transcription at exon 1 and begins translation at exon 3. Muscle-specific isoforms (2, 3, and 4) begin transcription at exon 2. Minor isoforms (5 and 6) begin further within the gene. Reporter assays revealed that promoter region 1 (for isoform 1) was functional in liver, muscle, and ovary, while promoter region 2 (for isoforms 2, 3, and 4) was active only in muscle cells. The authors concluded that the human AGL gene contains at least 2 promoter regions that confer differential expression of isoform mRNAs in a tissue-specific manner.
Cheng et al. (2007) showed that malin (NHLRC1; 608072), an E3 ubiquitin ligase mutated in Lafora disease (254780), interacted with mouse Agl and promoted its ubiquitination. Transfection studies in HepG2 cells showed that Agl was cytoplasmic, whereas malin was predominantly nuclear. However, after depletion of glycogen stores, about 90% of transfected cells exhibited partial nuclear Agl staining. Elevation of cAMP increased malin levels and malin/Agl complex formation. Refeeding mice for 2 hours after overnight fasting reduced hepatic Agl levels by 48%. Cheng et al. (2007) concluded that binding of glycogen regulates the stability of AGL and that ubiquitination of AGL may play a role in the pathophysiology of both Lafora disease and Cori disease (232400).
Bao et al. (1996) determined that the AGL gene is encoded by 35 exons spanning 85 kb of genomic DNA.
Yang-Feng et al. (1992) mapped the AGL gene to chromosome 1p21 by somatic cell hybrid analysis and in situ hybridization.
In 3 unrelated patients with glycogen storage disease IIIb (GSD3B; 232400), Shen et al. (1996) identified homozygous or compound heterozygous mutations in the AGL gene (see, e.g., 610860.0002-610860.0004). One of the mutations (c.17_18delAG; 610860.0004) was found in 8 of 10 additional GSD IIIb patients. Mutations in exon 3 were present in 12 of 13 GSD IIIb patients, suggesting a specific association.
Shen et al. (1997) identified a homozygous mutation in the AGL gene (610860.0001) in a child with an unusually severe GSD IIIa (GSD3A; 232400) phenotype.
Okubo et al. (1998) identified a homozygous mutation in the AGL gene (610860.0006) in a Japanese patient with GSD IIIb.
Hadjigeorgiou et al. (1999) reported 4 adult Italian patients with GSD IIIa. All of the patients had a history of infantile hepatomegaly followed by myopathy in their twenties. AGL activity and protein were almost absent in muscle specimens. RT-PCR revealed truncated muscle AGL cDNA in all 4 patients due to skipping of different exons. Hadjigeorgiou et al. (1999) commented that the AGL gene mutations described to date account for less than half of the total mutant alleles.
In Japan, Okubo et al. (2000) investigated 8 Japanese GSD IIIa patients from 7 families and identified 7 mutations, including 1 splicing mutation (610860.0007) that they had previously reported (Okubo et al., 1996), together with 6 novel ones.
Shaiu et al. (2000) reported 2 frequent mutations, each of which was found in the homozygous state in multiple patients, and each of which was associated with a subset of clinical phenotype in those patients with that mutation. One mutation, IVS32-12A-G (610860.0006), was identified in homozygosity in a confirmed GSD IIIa Caucasian patient who presented with mild clinical symptoms. This mutation had an allele frequency of approximately 5.5% in GSD III patients tested. The other common mutation, 3964delT (610860.0010), was identified in an African American patient who had a severe phenotype and early onset of clinical symptoms. The mutation was later identified in several other patients and was observed at a frequency of approximately 6.7%. Together, these 2 mutations can account for more than 12% of the molecular defects in GSD III patients. Shaiu et al. (2000) also identified 6 additional mutations and reviewed the nonmutation state.
Lucchiari et al. (2002) identified 7 novel mutations of the AGL gene in patients with GSD IIIa in the Mediterranean area.
Endo et al. (2006) identified 9 different mutations in the AGL gene, including 6 novel mutations, among 9 patients with GSD III. The patients were from Germany, Canada, Afghanistan, Iran, and Turkey.
Aoyama et al. (2009) identified 10 different AGL mutations, including 8 novel mutations (see, e.g., 610860.0014 and 610860.0015), in 23 Turkish patients with GSD III, including GSD type IIIc (GSD3C; 232400). No genotype/phenotype correlations were observed.
Cheng et al. (2009) studied 4 rare AGL mutations, including G1448R (610860.0009), to determine the molecular basis of GSD III pathogenesis. The L620P mutation primarily abolished transferase activity in transfected cells, whereas the R1147G (610860.0014) mutation only impaired glucosidase function. The R1448R and Y1445ins mutations in the carbohydrate-binding domain (CBD) were more severe in nature, leading to significant loss of all enzymatic activities and carbohydrate binding ability, as well as enhancing targeting for proteasomal degradation. Cheng et al. (2009) concluded that inactivation of either enzymatic activity is sufficient to cause GSD III disease, and suggested that the CBD of AGL may play a major role to coordinate its functions and regulation by the ubiquitin-proteasome system.
In a child with an unusually severe phenotype of glycogen storage disease type IIIa (GSD3A; 232400) manifested in both liver and muscle, Shen et al. (1997) identified a homozygous 1-bp insertion (4529insA) in the 3-prime coding region of the AGL gene. The mutation created a termination codon at residue 1510 of their sequence. (They stated that amino acid residue 1510 in their study corresponded to residue 1493 of the Yang et al. (1992) sequence.) The child had recurrent hypoglycemia, seizures, severe cardiomegaly, and hepatomegaly, and died at 4 years of age.
In a 41-year-old patient with hepatic glycogen storage disease type III (GSD3B; 232400), but with no clinical or laboratory evidence of myopathy or cardiomyopathy, Shen et al. (1996) demonstrated compound heterozygosity for 2 mutations in the AGL gene: a 16C-T transition, resulting in a gln6-to-ter (Q6X) substitution and W680X (610860.0003).
In a 41-year-old patient with hepatic glycogen storage disease type III (GSD3B; 232400), but with no clinical or laboratory evidence of myopathy or cardiomyopathy, Shen et al. (1996) demonstrated compound heterozygosity for 2 mutations in the AGL gene: a 2039G-A transition, resulting in a trp680-to-ter (W680X) substitution, and Q6X (610860.0002).
In 10 of 13 patients with GSD IIIb (GSD3B; 232400), Shen et al. (1996) identified a 2-bp deletion (c.17_18delAG) in the AGL gene, resulting in a truncated protein.
In 13 patients with GSD III (GSD3A; 232400) from 11 families, Parvari et al. (1997) identified a homozygous 1-bp deletion (4455delT) in exon 34 of the AGL gene, resulting in a frameshift and truncation of the last 30 amino acid residues of the protein. All patients were of North African Jewish descent and had liver and muscle involvement. While all patients showed the characteristic features related to the liver enzyme deficiency, the peripheral muscular impairment varied from minimal to severe, with neuromuscular involvement. The mutation appeared to be ethnic-specific as it was not seen in 18 patients of different ethnic origins.
In a 31-year-old Japanese female with GSD type IIIb (GSD3B; 232400), Okubo et al. (1998) detected a homozygous A-to-G transition in the AGL gene 12 bp upstream of exon 33 that caused activation of a cryptic splice site and insertion of an extra 11 bp of intronic sequence between exons 32 and 33. The mutation was predicted to change the last 15 consecutive C-terminal amino acids before premature termination at codon 1436 and loss of 112 terminal amino acids. The patient's parents were first cousins.
Shaiu et al. (2000) identified this mutation in homozygosity in a GSD type IIIa (GSD3A; 232400) Caucasian patient presenting with mild clinical symptoms. They found that the IVS32-12A-G mutation had an allelic frequency of about 5.5% in the GSD III patients tested.
In a Japanese man with glycogen storage disease type IIIa (GSD3A; 232400), Okubo et al. (1996) reported heterozygosity for a 124-bp deletion in the AGL gene, corresponding to a single exon. The deletion resulted from a G-to-T transversion at the donor splice site immediately downstream of the deletion. The mutation was predicted to result in a truncated enzyme. This was the first mutation in the AGL gene identified in a patient with GSD III. The patient was a 43-year-old Japanese man who had been diagnosed with GSD III at 18 years of age. He had hepatomegaly and muscle weakness. Family history showed no consanguinity. The patient's asymptomatic father and son were also heterozygous for the mutation. Southern blot analysis of the patient's genomic DNA showed an additional, unique EcoRI fragment of 5.8 kb, inherited from the mother (610860.0008).
See 610860.0007 and Okubo et al. (1996).
In a Japanese patient, born from a consanguineous family, with GSD IIIa (GSD3A; 232400), Okubo et al. (1999) identified a homozygous 4742G-C transversion in exon 33 of the AGL gene, resulting in a gly1448-to-arg (G1448R) substitution in a putative glycogen-binding site that is indispensable for enzyme activity. The authors claimed that this was the first report of a missense mutation associated with GSD III.
Cheng et al. (2007) showed that mouse Agl with the G1448R mutation was unable to bind glycogen and displayed decreased stability that was rescued by proteasome inhibition. Agl G1148R was more highly ubiquitinated than wildtype Agl.
In a 25-year-old African American female with GSD IIIa (GSD3A; 232400), Shaiu et al. (2000) identified a homozygous 1-bp deletion (3964delT) in the AGL gene. She presented with hepatomegaly, symptomatic hypoglycemia, and failure to thrive at 1 year of age. Muscle involvement as truncal hypotonia and proximal upper and lower extremity weakness were noted since 7 years of age, with CPK values ranging from 300 to 1,000 IU. At 25 years of age, progressive myopathy, hepatomegaly, and repeated episodes of hypoglycemia were apparent. This mutation was subsequently identified in homozygosity in several patients with similar presentation and had an overall frequency of around 6.7% in the GSD III patients tested.
In a 2-year-old patient of mixed Asian ancestry with glycogen storage disease type IIIb (GSD3B; 232400), Okubo et al. (2000) observed compound heterozygosity for 2 mutations in the AGL gene: a deletion of 2399C in exon 16 inherited from the Japanese father, and a G-to-A transition at position +5 at the donor splice site of intron 33 (610860.0012) inherited from the Chinese mother. The girl had been admitted to hospital because of liver dysfunction. Hepatomegaly was first noted at age 4 months. She had experienced occasional hypoglycemia, and growth retardation was noted. Muscular manifestations were not described.
For discussion of the splice site mutation in the AGL gene that was found in compound heterozygous state in a patient with glycogen storage disease type IIIb (GSD3B; 232400) by Okubo et al. (2000), see 610860.0011.
In 6 children from 5 families with GSD IIIa (GSD3A; 232400) from the Faroe Islands, Santer et al. (2001) identified a homozygous 1222C-T transition in the AGL gene, resulting in an arg408-to-ter substitution (R408X). All patients were homozygous for the same haplotype defined by 5 intragenic polymorphisms, supporting a founder effect. The R408X mutation was also detected in compound heterozygosity in 2 of 50 GSD IIIa patients of other European or North American origin. Whereas the mutation was not detected in 198 German newborns, 9 of 272 Faroese newborns were heterozygous, predicting a carrier frequency of 1 in 30 and a calculated prevalence of 1 per 3,600 in the Faroese population. The population of 45,000 of this small archipelago in the North Atlantic has its roots in the colonization by Norwegians in the 8th century and throughout the Viking Age. Santer et al. (2001) concluded that due to a founder effect, the Faroe Islands have the highest prevalence of GSD IIIa worldwide.
In a 14-year-old Turkish girl with isolated glucosidase deficiency, known as glycogen storage disease type IIIc (GSD3C; 232400), Aoyama et al. (2009) identified a homozygous 3439A-G transition in exon 27 of the AGL gene, resulting in an arg1147-to-gly (R1147G) substitution in a conserved residue in the C-terminal region. The patient had mild hepatomegaly, but did not have hypoglycemia or clinical muscle involvement. Cheng et al. (2009) showed that the R1147G-mutant protein lost glucosidase activity, but retained 40% of transferase activity compared to wildtype.
In 6 Turkish patients with glycogen storage disease type IIIa (GSD3A; 232400), Aoyama et al. (2009) identified a homozygous 3980G-A transition in exon 31 of the AGL gene, resulting in a trp1327-to-ter (W1327X) substitution. All 6 patients were from 2 cities in the eastern Black Sea region, and haplotype analysis indicated a founder effect.
Aoyama, Y., Ozer, I., Demirkol, M., Ebara, T., Murase, T., Podskarbi, T., Shin, Y. S., Gokcay, G., Okubo, M. Molecular features of 23 patients with glycogen storage disease type III in Turkey: a novel mutation p.R1147G associated with isolated glucosidase deficiency, along with 9 AGL mutations. J. Hum. Genet. 54: 681-686, 2009. [PubMed: 19834502] [Full Text: https://doi.org/10.1038/jhg.2009.100]
Bao, Y., Dawson, T. L., Jr., Chen, Y.-T. Human glycogen debranching enzyme gene (AGL): complete structural organization and characterization of the 5-prime flanking region. Genomics 38: 155-165, 1996. [PubMed: 8954797] [Full Text: https://doi.org/10.1006/geno.1996.0611]
Cheng, A., Zhang, M., Gentry, M. S., Worby, C. A., Dixon, J. E., Saltiel, A. R. A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori's disease. Genes Dev. 21: 2399-2409, 2007. [PubMed: 17908927] [Full Text: https://doi.org/10.1101/gad.1553207]
Cheng, A., Zhang, M., Okubo, M., Omichi, K., Saltiel, A. R. Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions. Hum. Molec. Genet. 18: 2045-2052, 2009. [PubMed: 19299494] [Full Text: https://doi.org/10.1093/hmg/ddp128]
Endo, Y., Horinishi, A., Vorgerd, M., Aoyama, Y., Ebara, T., Murase, T., Odawara, M., Podskarbi, T., Shin, Y. S., Okubo, M. Molecular analysis of the AGL gene: heterogeneity of mutations in patients with glycogen storage disease type III from Germany, Canada, Afghanistan, Iran, and Turkey. J. Hum. Genet. 51: 958-963, 2006. [PubMed: 17047887] [Full Text: https://doi.org/10.1007/s10038-006-0045-x]
Hadjigeorgiou, G. M., Comi, G. P., Bordoni, A., Shen, J., Chen, Y.-T., Salani, S., Toscano, A., Fortunato, F., Lucchiari, S., Bresolin, N., Rodolico, C., Piscaglia, M. G., Franceschina, L., Papadimitriou, A., Scarlato, G. Novel donor splice site mutations of AGL gene in glycogen storage disease type IIIa. J. Inherit. Metab. Dis. 22: 762-763, 1999. [PubMed: 10472540] [Full Text: https://doi.org/10.1023/a:1005572906807]
Lucchiari, S., Fogh, I., Prelle, A., Parini, R., Bresolin, N., Melis, D., Fiori, L., Scarlato, G., Comi, G. P. Clinical and genetic variability of glycogen storage disease type IIIa: seven novel AGL gene mutations in the Mediterranean area. Am. J. Med. Genet. 109: 183-190, 2002. [PubMed: 11977176] [Full Text: https://doi.org/10.1002/ajmg.10347]
Okubo, M., Aoyama, Y., Murase, T. A novel donor splice site mutation in the glycogen debranching enzyme gene is associated with glycogen storage disease type III. Biochem. Biophys. Res. Commun. 224: 493-499, 1996. Note: Erratum: Biochem. Biophys. Res. Commun. 225: 695 only, 1996. [PubMed: 8702417] [Full Text: https://doi.org/10.1006/bbrc.1996.1055]
Okubo, M., Horinishi, A., Makamura, N., Aoyama, Y., Hashimoto, M., Endo, Y., Murase, T. A novel point mutation in an acceptor splice site of intron 32 (IVS32 A-12-to-G) but no exon 3 mutations in the glycogen debranching enzyme gene in a homozygous patient with glycogen storage disease type IIIb. Hum. Genet. 102: 1-5, 1998. [PubMed: 9490286] [Full Text: https://doi.org/10.1007/s004390050646]
Okubo, M., Horinishi, A., Suzuki, Y., Murase, T., Hayasaka, K. Compound heterozygous patient with glycogen storage disease type III: identification of two novel AGL mutations, a donor splice site mutation of Chinese origin and a 1-bp deletion of Japanese origin. Am. J. Med. Genet. 93: 211-214, 2000. [PubMed: 10925384] [Full Text: https://doi.org/10.1002/1096-8628(20000731)93:3<211::aid-ajmg10>3.0.co;2-z]
Okubo, M., Horinishi, A., Takeuchi, M., Suzuki, Y., Sakura, N., Hasegawa, Y., Igarashi, T., Goto, K., Tahara, H., Uchimoto, S., Omichi, K., Kanno, H., Hayasaka, K., Murase, T. Heterogeneous mutations in the glycogen-debranching enzyme gene are responsible for glycogen storage disease type IIIa in Japan. Hum. Genet. 106: 108-115, 2000. [PubMed: 10982190] [Full Text: https://doi.org/10.1007/s004390051017]
Okubo, M., Kanda, F., Horinishi, A., Takahashi, K., Okuda, S., Chihara, K., Murase, T. Glycogen storage disease type IIIa: first report of a causative missense mutation (G1448R) of the glycogen debranching enzyme gene found in a homozygous patient. (Abstract) Hum. Mutat. 14: 542-543, 1999. [PubMed: 10571954] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(199912)14:6<542::AID-HUMU15>3.0.CO;2-0]
Parvari, R., Moses, S., Shen, J., Hershkovitz, E., Lerner, A., Chen, Y.-T. A single-base deletion in the 3-prime coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients. Europ. J. Hum. Genet. 5: 266-270, 1997. [PubMed: 9412782]
Santer, R., Kinner, M., Steuerwald, U., Kjaergaard, S., Skovby, F., Simonsen, H., Shaiu, W.-L., Chen, Y.-T., Schneppenheim, R., Schaub, J. Molecular genetic basis and prevalence of glycogen storage disease type IIIA in the Faroe Islands. Europ. J. Hum. Genet. 9: 388-391, 2001. [PubMed: 11378828] [Full Text: https://doi.org/10.1038/sj.ejhg.5200632]
Shaiu, W.-L., Kishnani, P. S., Shen, J., Liu, H.-M., Chen, Y.-T. Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease. Molec. Genet. Metab. 69: 16-23, 2000. [PubMed: 10655153] [Full Text: https://doi.org/10.1006/mgme.1999.2953]
Shen, J,, Bao, Y., Chen, Y.-T. A nonsense mutation due to a single base insertion in the 3-prime-coding region of glycogen debranching enzyme gene associated with a severe phenotype in a patient with glycogen storage disease type IIIa. Hum. Mutat. 9: 37-40, 1997. [PubMed: 8990006] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)9:1<37::AID-HUMU6>3.0.CO;2-M]
Shen, J., Bao, Y., Liu, H.-M., Lee, P., Leonard, J. V., Chen, Y.-T. Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle. J. Clin. Invest. 98: 352-357, 1996. [PubMed: 8755644] [Full Text: https://doi.org/10.1172/JCI118799]
Yang, B. Z., Ding, J. H., Enghild, J. J., Bao, Y., Chen, Y. T. Molecular cloning and nucleotide sequence of cDNA encoding human muscle glycogen debranching enzyme. J. Biol. Chem. 267: 9294-9299, 1992. [PubMed: 1374391]
Yang, B.-Z., Ding, J.-H., Bao, Y., Eason, J. F. M., Chen, Y.-T. Molecular basis of the enzymatic variability in type III glycogen storage disease (GSD-III). (Abstract) Am. J. Hum. Genet. 51 (suppl.): A28, 1992.
Yang-Feng, T. L., Zheng, K., Yu, J., Yang, B.-Z., Chen, Y.-T., Kao, F.-T. Assignment of the human glycogen debrancher gene to chromosome 1p21. Genomics 13: 931-934, 1992. [PubMed: 1505983] [Full Text: https://doi.org/10.1016/0888-7543(92)90003-b]