Abstract
Fabry disease is caused by an α-galactosidase A (GLA) deficiency. In this study, we identified 28 unrelated Korean families with Fabry disease with 25 distinct mutations in the GLA gene including six novel mutations (p.W47X, p.C90X, p.D61EfsX32, IVS4−11T>A, p.D322E and p.W349). Notably, five subjects from four unrelated families carried the p.E66Q variant, previously known as a pathogenic mutation in atypical Fabry disease. Among these patients, only one had proteinuria and two had hypertrophic cardiomyopathy without any other systemic manifestation of Fabry disease. Substantial residual GLA activity was shown both in the leukocytes of p.E66Q patients (19.0–30.3% of normal activity) and in transiently overexpressed COS-7 cells (43.8±3.03% of normal activity). Although GLA harboring p.E66Q is unstable at neutral pH, the enzyme is efficiently expressed in the lysosomes of COS-7 cells. The location of p.E66 is distant from both the active site and the dimer interface, and has a more accessible surface area than have other mutations of atypical Fabry disease. In addition, the allele frequency of p.E66Q determined in 833 unrelated Korean individuals was remarkably high at 1.046% (95% confidence interval, 0.458–1.634%). These results indicate that p.E66Q is a functional polymorphism rather than a pathogenic mutation.
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References
Kornreich, R., Desnick, R. J. & Bishop, D. F. Nucleotide sequence of the human alpha-galactosidase A gene. Nucleic Acids Res. 17, 3301–3302 (1989).
Meikle, P. J., Hopwood, J. J., Clague, A. E. & Carey, W. F. Prevalence of lysosomal storage disorders. JAMA 281, 249–254 (1999).
Zarate, Y. A. & Hopkin, R. J. Fabry's disease. Lancet 372, 1427–1435 (2008).
Hwu, W. L., Chien, Y. H., Lee, N. C., Chiang, S. C., Dobrovolny, R., Huang, A. C. et al. Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A). Hum. Mutat. 30, 1397–1405 (2009).
Spada, M., Pagliardini, S., Yasuda, M., Tukel, T., Thiagarajan, G., Sakuraba, H. et al. High incidence of later-onset fabry disease revealed by newborn screening. Am. J. Hum. Genet. 79, 31–40 (2006).
Eng, C. M., Germain, D. P., Banikazemi, M., Warnock, D. G., Wanner, C., Hopkin, R. J. et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet. Med. 8, 539–548 (2006).
Ishii, S., Kase, R., Sakuraba, H. & Suzuki, Y. Characterization of a mutant alpha-galactosidase gene product for the late-onset cardiac form of Fabry disease. Biochem. Biophys. Res. Commun. 197, 1585–1589 (1993).
Nakao, S., Takenaka, T., Maeda, M., Kodama, C., Tanaka, A., Tahara, M. et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl. J. Med. 333, 288–293 (1995).
Yoshitama, T., Nakao, S., Takenaka, T., Teraguchi, H., Sasaki, T., Kodama, C. et al. Molecular genetic, biochemical, and clinical studies in three families with cardiac Fabry's disease. Am. J. Cardiol. 87, 71–75 (2001).
Monserrat, L., Gimeno-Blanes, J. R., Marin, F., Hermida-Prieto, M., Garcia-Honrubia, A., Perez, I. et al. Prevalence of fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 50, 2399–2403 (2007).
Nakao, S., Kodama, C., Takenaka, T., Tanaka, A., Yasumoto, Y., Yoshida, A. et al. Fabry disease: detection of undiagnosed hemodialysis patients and identification of a ‘renal variant’ phenotype. Kidney Int. 64, 801–807 (2003).
Kotanko, P., Kramar, R., Devrnja, D., Paschke, E., Voigtlander, T., Auinger, M. et al. Results of a nationwide screening for Anderson-Fabry disease among dialysis patients. J. Am. Soc. Nephrol. 15, 1323–1329 (2004).
Tanaka, M., Ohashi, T., Kobayashi, M., Eto, Y., Miyamura, N., Nishida, K. et al. Identification of Fabry's disease by the screening of alpha-galactosidase A activity in male and female hemodialysis patients. Clin. Nephrol. 64, 281–287 (2005).
Ichinose, M., Nakayama, M., Ohashi, T., Utsunomiya, Y., Kobayashi, M. & Eto, Y. Significance of screening for Fabry disease among male dialysis patients. Clin. Exp. Nephrol. 9, 228–232 (2005).
Rolfs, A., Bottcher, T., Zschiesche, M., Morris, P., Winchester, B., Bauer, P. et al. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet 366, 1794–1796 (2005).
Ishii, S., Suzuki, Y. & Fan, J. Q. Role of Ser-65 in the activity of alpha-galactosidase A: characterization of a point mutation (S65T) detected in a patient with Fabry disease. Arch. Biochem. Biophys. 377, 228–233 (2000).
Ishii, S., Chang, H. H., Kawasaki, K., Yasuda, K., Wu, H. L., Garman, S. C. et al. Mutant alpha-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin. Biochem J. 406, 285–295 (2007).
Kase, R., Bierfreund, U., Klein, A., Kolter, T., Utsumi, K., Itoha, K. et al. Characterization of two alpha-galactosidase mutants (Q279E and R301Q) found in an atypical variant of Fabry disease. Biochim. Biophys. Acta. 1501, 227–235 (2000).
Park, J. Y., Kim, G. H., Kim, S. S., Ko, J. M., Lee, J. J. & Yoo, H. W. Effects of a chemical chaperone on genetic mutations in alpha-galactosidase A in Korean patients with Fabry disease. Exp. Mol. Med. 41, 1–7 (2009).
Okumiya, T., Ishii, S., Takenaka, T., Kase, R., Kamei, S., Sakuraba, H. et al. Galactose stabilizes various missense mutants of alpha-galactosidase in Fabry disease. Biochem. Biophys. Res. Commun. 214, 1219–1224 (1995).
Choi, J. H., Cho, Y. M., Suh, K. S., Yoon, H. R., Kim, G. H., Kim, S. S. et al. Short-term efficacy of enzyme replacement therapy in Korean patients with Fabry disease. J. Korean Med. Sci. 23, 243–250 (2008).
Lee, J. K., Kim, G. H., Kim, J. S., Kim, K. K., Lee, M. C. & Yoo, H. W. Identification of four novel mutations in five unrelated Korean families with Fabry disease. Clin. Genet. 58, 228–233 (2000).
Kayganich, K. A. & Murphy, R. C. Fast atom bombardment tandem mass spectrometric identification of diacyl, alkylacyl, and alk-1-enylacyl molecular species of glycerophosphoethanolamine in human polymorphonuclear leukocytes. Anal. Chem. 64, 2965–2971 (1992).
Bligh, E. G. & Dyer, W. J. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911–917 (1959).
Desnick, R. J., Allen, K. Y., Desnick, S. J., Raman, M. K., Bernlohr, R. W. & Krivit, W. Fabry's disease: enzymatic diagnosis of hemizygotes and heterozygotes. Alpha-galactosidase activities in plasma, serum, urine, and leukocytes. J. Lab. Clin. Med. 81, 157–171 (1973).
Schafer, E., Baron, K., Widmer, U., Deegan, P., Neumann, H. P., Sunder-Plassmann, G. et al. Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease. Hum. Mutat. 25, 412 (2005).
Sachdev, B., Takenaka, T., Teraguchi, H., Tei, C., Lee, P., McKenna, W. J. et al. Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation 105, 1407–1411 (2002).
Okuda, S. Renal involvement in Fabry's disease. Intern. Med. 39, 601–602 (2000).
Ries, M., Gupta, S., Moore, D. F., Sachdev, V., Quirk, J. M., Murray, G. J. et al. Pediatric Fabry disease. Pediatrics 115, e344–e355 (2005).
Ries, M., Ramaswami, U., Parini, R., Lindblad, B., Whybra, C., Willers, I. et al. The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents. Eur. J. Pediatr. 162, 767–772 (2003).
Garman, S. C. Structure-function relationships in alpha-galactosidase A. Acta. Paediatr. Suppl. 96, 6–16 (2007).
Garman, S. C. & Garboczi, D. N. The molecular defect leading to Fabry disease: structure of human alpha-galactosidase. J. Mol. Biol. 337, 319–335 (2004).
Yasuda, M., Shabbeer, J., Benson, S. D., Maire, I., Burnett, R. M. & Desnick, R. J. Fabry disease: characterization of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele. Hum. Mutat. 22, 486–492 (2003).
Ledvinova, J., Poupetova, H., Hanackova, A., Pisacka, M. & Elleder, M. Blood group B glycosphingolipids in alpha-galactosidase deficiency (Fabry disease): influence of secretor status. Biochim. Biophys. Acta. 1345, 180–187 (1997).
Acknowledgements
We thank the patients and their families for participating in this study, which was supported by a grant from the Korean Ministry for Health, Welfare and Family Affairs (Grant no. A080588).
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Lee, B., Heo, S., Kim, GH. et al. Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns. J Hum Genet 55, 512–517 (2010). https://doi.org/10.1038/jhg.2010.58
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DOI: https://doi.org/10.1038/jhg.2010.58
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