NOVEL MUTATIONS OF THE G6PC GENE IN MALAYSIANS WITH GLYCOGEN STORAGE DISEASE 1a (GSD1a)
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Published:
Feb 28, 2021
Keywords:
Glycogen storage disease type 1a (GSD1a) glucose-6-phosphatase enzyme (G6Pase) Glucose-6-Phosphate catalytic subunit (G6PC)
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Abstract
Abstract
Glycogen Storage Disease 1a is a rare autosomal recessive disorder caused by mutations in the glucose-6-phosphatase gene (G6PC) encoding glucose-6-phosphatase (G6Pase), a key enzyme for the maintenance of glucose homeostasis. Deficiency of G6Pase underlies this disease associated with life-threatening hypoglycemia and growth retardation. To date, more than 110 mutations have be found worldwide.The aims of this study are to identify the mutations in G6PC gene in Malaysian GSD1a patients using standard molecular genetics methods and to determine the pathogenicity level of the novel mutations. We performed mutation screening for 21 GSD1a unrelated patients (Malay n=14; Chinese n=7) using Polymerase Chain Reaction (PCR) and DNA sequencing. Genomic DNA was extracted from patients’ peripheral blood and all five G6PC exons were amplified using specific primers. Nine mutations were found, in which five mutations have been previously reported and four are potentially novel mutations (H52L, K76X, P113S and A346P). To obtain further evidence on the potential pathogenicity of the novel mutations, restriction enzyme assay and TaqMan genotyping assay were designed to investigate its allele frequency in a panel of healthy individuals that serves as the control population samples (n=50 Malays, n=50 Chinese, n=50 Indians). Restriction enzymes MseI and MboI were used to assay the K76X and P113S mutations respectively. For the other two mutations (H52L and A346P), TaqMan genotyping assays was employed due to inavailability of a suitable restriction enzyme to distinguish between the normal and mutant sequences. Results obtained from both the restriction enzymes assays and the TaqMan assays showed that no mutant allele could be found in all 150 healthy individuals (300 alleles). In conclusion, four yet unreported mutations have been found in the Malaysian population, and these mutations are potentially novel pathogenic mutations. These finding provide support that the mutations spectrum of G6PC gene in Malaysia is heterogeneous, at least among the Chinese and Malay populations.
KEY WORDS: Glycogen storage disease type 1a (GSD1a); glucose-6-phosphatase enzyme (G6Pase); Glucose-6-Phosphate catalytic subunit (G6PC).
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Abd Rahman, A. A., Abdullah, I. S., Ser Huy, T., Khaidizar, F. D., Yap, S., Wee Teik, K., Lock Hock, N., Hui Bein, C., Pei Tee, O., & Mohamed, Z. (2021). NOVEL MUTATIONS OF THE G6PC GENE IN MALAYSIANS WITH GLYCOGEN STORAGE DISEASE 1a (GSD1a). Malaysian Journal of Science, 40(1), 34–45. https://doi.org/10.22452/mjs.vol40no1.3
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References
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Chen, Y. T. (2001). Glycogen storage disease. In Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D. (Eds.), The metabolic and molecular bases of inherited diseases, (8th Ed.) (pp 1521-1551). New York, NY: McGraw-Hill.
Chou, J. Y and Mansfield, B. C. (1999). Molecular Genetics of Type I Glycogen Storage Diseases. Trends Endocrinol Metabolism, 10: 104-113.
Chou, J. Y., Hemrika, W., Annabi, B., Lei, K. J and Pan C. Y. (1998). Transmembrane topology of glucose-6-phosphatase. Journal of Biology and Chemistry, 273: 6144–6148.
Chou, J.Y., Jun, H.S. and Mansfield, B.C. (2010) Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy. Nat. Rev. Endocrinol, 6:676–688.
Ekstein, J., Rubin, Berish.Y, Anderson, S.L., Weinstein, D.A., Bach, G., Abeliovich, D., Webb M and Risch, Neil. (2004). Mutation Frequencies for Glycogen Storage Disease Ia in the Ashkenazi Jewish Population. American Journal of Medical Genetics, 129A: 162–164
Franco, L. M., Krishnamurthy, V., Bali, D., Weinstein, D. A., Clary, B., Boney, A., &d Kishnani, P. S. (2005a). Hepatocellular carcinoma in glycogen storage disease type 1a: A cases series. Journal of Inherited Metabolite Disorders, 28, 153-162.
Froissart, R., Piraud, M., Boudjemline, A. M., Vianey-Saban, C., Petit, R., Hubert-Buron, A., Eberschweiler, P. T., Gajdos, V and Labrune. (2011). Glucose-6-phosphatase deficiency. Orphanet Journal of Rare Disorders, 6: 27.
Janecke, A. R., Mayatepek, E., & Utermann, G. (2001). Minireview: Molecular genetics of type 1 glycogen storage disease. Molecular Genetic Metabolism, 73:117-125.
Kajihara, S., Matsuhashi, S., Yamamoto, K., Kido, K., Tsuji, K., Tanae, A., Fujiyama, S., Itoh, T., Tanigawa, K., Uchida, M., Setoguchi, Y., Motomura, M., Mizuta, T and Sakai, T. (1995). Exon Redefinition by a Point Mutation within Exon 5 of the Glucose-6-Phosphatase Gene Is the Major Cause of Glycogen Storage Disease Type Ia in Japan. Am. J. Hum. Genet, 57: 549-555.
Kim, Y., Choi, J., Lee, B., Kim, G., Kim, K., Yoo, H. (2020) Predominance of the c.648G > T G6PC gene mutation and late complications in Korean patients with glycogen storage disease type Ia. Orphanet J Rare Dis 15: 45 https://doi.org/ 10.1186/s13023-020-1321-0
Lam, C. W., But, W. M., Shek, C. C., Tong, S. F., Chan, Y. S., Choy, K. W., Tse, W. Y., Pang, C. P and Hjelm, N. M. (1998). Glucose-6-phosphatase gene (727G-->T) splicing mutation is prevalent in Hong Kong Chinese patients with glycogen storage disease type 1a. Clinical of Genetics, 53: 184-190.
Lei, K. J., Chen, Y. T., Chen, H., Wong, L. J., Liu, J. L., McConkie-Rosell, A., Van Hove, J. L. K., Ou, H. C., Yeh, N. J., Pan, L. Y and Chou, J. Y. (1995). Genetic basis of glycogen storage disease type Ia: Prevalent mutations at the glucose-6-phosphatase locus. Am. J. Hum. Genet, 57: 766-771.
Lei, K. J., Pan, C. J., Shelly,L. L., Liu, J. L. & Chou, J. Y. (1994). Identification of mutations in the gene for glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type la. Journal of Clinical Investigation, 93:1994-1999.
Lei, K. J., Shelly, L. L., Pan, C. J, Sidbury, J. B., & Chou, J. Y. (1993). Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Science, 262:580-583.
Pan, C. J., Lei, K. J., Annabi, B., Hemrika, W and Chou, J. Y. (1998). Transmembrane Topology of Glucose-6-Phosphatase. Journal of Biology Chemistry, 273: 6144-6148.
Peter, G. A., Rake, S. J. P., Hasan, O., Akman., Salvatore, D. M. (2006). The Glycogen Storage Diseases and Related Disorders. Inborn Metabolic Diseases, 101-119.
PolyPhen-2: prediction of functional effects of human nsSNPs, http:// genetics.bwh.harvard.edu/pph2/
Rake, J.P., Berge, A.M., Visser, G. et al., (2000). Glycogen storage disease type Ia: recent experience with mutation analysis, a summary of mutations reported in the literature and a newly developed diagnostic flow chart. European Journal of Pediatrics, 159: 322-330.
Shelly, L. L., Lei, K. J., Pan, C. J. et al., (1993). Isolation of the gene for murine glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1A. Journal Biology Chemistry, 268: 21482-21485.
Shieh, J. J., Terzioglu, M., Hiraiwa, H., Marsh, J., Pan, C. J., Chen, L. Y and Chou, J. Y. (2002). The molecular basis of glycogen storage disease type 1a. Journal of Biology Chemistry, 277: 5047-5053.
The Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/gene.php?gene=G6PC.
Trioche, P., Francoual., Chalas, J., Capel, L., Bernard, O and Labrune, P. (1999). Identification of Three Novel Mutations (Q54P, W70X and T108I) in the Glucose-6-phosphatase Gene of Patients with Glycogen Storage Disease Type Ia. Human Mutation, 14: 91.
Wang, J., Hong, C., Chung, N. L., Wuh, L. H., Yin, H. C., William, J. C., Lee, J. W., Zhang, V. W. (2013). Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin. Genetic in Medicine, 15(2): 106-114.
Zheng, X. B., Qian, L., Mei, L., Yu, J. (2014). Three novel mutation of the G6PC gene identified in chinese patients with glycogen storage disease type 1a. European Journal of Pediatrics. DOI 10.1007/s00431-014-2354-y
Baker, K. E. and Parker, R. (2004). "Nonsense-mediated mRNA decay: Terminating erroneous gene expression". Current Opinion in Cell Biology. 16 (3): 293–299. doi:10.1016/j.ceb.2004.03.003. PMID 15145354.
Barkaoui, E., Cherif, W., Tebib, N., Charfeddine, C., Ben Rhouma, F., Azzouz, H., Ben Chehida, A., Monastiri, K., Chemli, J., Amri, F., Ben Turkia, H., Abdelmoula, M. S., Kaabachi, N., Abdelhak, S and Ben Dridi, M.F. (2007). Mutation spectrum of glycogen storage disease type Ia in Tunisia:
implication for molecular diagnosis. Journal Inherited Metabolism Disorder, 30(6):989.
Chen, Y. T & Burchell, A. (1999).Glycogen storage diseases. In: Scriver C. R., Beaudet A. L., Sly W. S., Vale D (Eds.), The metabolic and molecular bases of inherited diseases, (7th ed.) (pp. 925-965). New York, NY: McGraw-Hill.
Chen, Y. T. (2001). Glycogen storage disease. In Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D. (Eds.), The metabolic and molecular bases of inherited diseases, (8th Ed.) (pp 1521-1551). New York, NY: McGraw-Hill.
Chou, J. Y and Mansfield, B. C. (1999). Molecular Genetics of Type I Glycogen Storage Diseases. Trends Endocrinol Metabolism, 10: 104-113.
Chou, J. Y., Hemrika, W., Annabi, B., Lei, K. J and Pan C. Y. (1998). Transmembrane topology of glucose-6-phosphatase. Journal of Biology and Chemistry, 273: 6144–6148.
Chou, J.Y., Jun, H.S. and Mansfield, B.C. (2010) Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy. Nat. Rev. Endocrinol, 6:676–688.
Ekstein, J., Rubin, Berish.Y, Anderson, S.L., Weinstein, D.A., Bach, G., Abeliovich, D., Webb M and Risch, Neil. (2004). Mutation Frequencies for Glycogen Storage Disease Ia in the Ashkenazi Jewish Population. American Journal of Medical Genetics, 129A: 162–164
Franco, L. M., Krishnamurthy, V., Bali, D., Weinstein, D. A., Clary, B., Boney, A., &d Kishnani, P. S. (2005a). Hepatocellular carcinoma in glycogen storage disease type 1a: A cases series. Journal of Inherited Metabolite Disorders, 28, 153-162.
Froissart, R., Piraud, M., Boudjemline, A. M., Vianey-Saban, C., Petit, R., Hubert-Buron, A., Eberschweiler, P. T., Gajdos, V and Labrune. (2011). Glucose-6-phosphatase deficiency. Orphanet Journal of Rare Disorders, 6: 27.
Janecke, A. R., Mayatepek, E., & Utermann, G. (2001). Minireview: Molecular genetics of type 1 glycogen storage disease. Molecular Genetic Metabolism, 73:117-125.
Kajihara, S., Matsuhashi, S., Yamamoto, K., Kido, K., Tsuji, K., Tanae, A., Fujiyama, S., Itoh, T., Tanigawa, K., Uchida, M., Setoguchi, Y., Motomura, M., Mizuta, T and Sakai, T. (1995). Exon Redefinition by a Point Mutation within Exon 5 of the Glucose-6-Phosphatase Gene Is the Major Cause of Glycogen Storage Disease Type Ia in Japan. Am. J. Hum. Genet, 57: 549-555.
Kim, Y., Choi, J., Lee, B., Kim, G., Kim, K., Yoo, H. (2020) Predominance of the c.648G > T G6PC gene mutation and late complications in Korean patients with glycogen storage disease type Ia. Orphanet J Rare Dis 15: 45 https://doi.org/ 10.1186/s13023-020-1321-0
Lam, C. W., But, W. M., Shek, C. C., Tong, S. F., Chan, Y. S., Choy, K. W., Tse, W. Y., Pang, C. P and Hjelm, N. M. (1998). Glucose-6-phosphatase gene (727G-->T) splicing mutation is prevalent in Hong Kong Chinese patients with glycogen storage disease type 1a. Clinical of Genetics, 53: 184-190.
Lei, K. J., Chen, Y. T., Chen, H., Wong, L. J., Liu, J. L., McConkie-Rosell, A., Van Hove, J. L. K., Ou, H. C., Yeh, N. J., Pan, L. Y and Chou, J. Y. (1995). Genetic basis of glycogen storage disease type Ia: Prevalent mutations at the glucose-6-phosphatase locus. Am. J. Hum. Genet, 57: 766-771.
Lei, K. J., Pan, C. J., Shelly,L. L., Liu, J. L. & Chou, J. Y. (1994). Identification of mutations in the gene for glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type la. Journal of Clinical Investigation, 93:1994-1999.
Lei, K. J., Shelly, L. L., Pan, C. J, Sidbury, J. B., & Chou, J. Y. (1993). Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Science, 262:580-583.
Pan, C. J., Lei, K. J., Annabi, B., Hemrika, W and Chou, J. Y. (1998). Transmembrane Topology of Glucose-6-Phosphatase. Journal of Biology Chemistry, 273: 6144-6148.
Peter, G. A., Rake, S. J. P., Hasan, O., Akman., Salvatore, D. M. (2006). The Glycogen Storage Diseases and Related Disorders. Inborn Metabolic Diseases, 101-119.
PolyPhen-2: prediction of functional effects of human nsSNPs, http:// genetics.bwh.harvard.edu/pph2/
Rake, J.P., Berge, A.M., Visser, G. et al., (2000). Glycogen storage disease type Ia: recent experience with mutation analysis, a summary of mutations reported in the literature and a newly developed diagnostic flow chart. European Journal of Pediatrics, 159: 322-330.
Shelly, L. L., Lei, K. J., Pan, C. J. et al., (1993). Isolation of the gene for murine glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1A. Journal Biology Chemistry, 268: 21482-21485.
Shieh, J. J., Terzioglu, M., Hiraiwa, H., Marsh, J., Pan, C. J., Chen, L. Y and Chou, J. Y. (2002). The molecular basis of glycogen storage disease type 1a. Journal of Biology Chemistry, 277: 5047-5053.
The Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/gene.php?gene=G6PC.
Trioche, P., Francoual., Chalas, J., Capel, L., Bernard, O and Labrune, P. (1999). Identification of Three Novel Mutations (Q54P, W70X and T108I) in the Glucose-6-phosphatase Gene of Patients with Glycogen Storage Disease Type Ia. Human Mutation, 14: 91.
Wang, J., Hong, C., Chung, N. L., Wuh, L. H., Yin, H. C., William, J. C., Lee, J. W., Zhang, V. W. (2013). Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin. Genetic in Medicine, 15(2): 106-114.
Zheng, X. B., Qian, L., Mei, L., Yu, J. (2014). Three novel mutation of the G6PC gene identified in chinese patients with glycogen storage disease type 1a. European Journal of Pediatrics. DOI 10.1007/s00431-014-2354-y