Abstract
Fabry disease is a genetic disorder caused by deficient activity of lysosomal enzyme α-galactosidase A (GLA) and end-stage renal disease (ESRD) will be present after accumulation of glycosphingolipids within the kidney. Undiagnosed atypical variants of Fabry disease, which are limited to renal involvement, were found in several ESRD patient populations. On the other hand, unexpectedly high frequencies of male subjects having the c.196G>C nucleotide change (p.E66Q) showing low α-GLA activity have been reported on Japanese and Korean screening for Fabry disease. However, several evidences indicate the c.196G>C is not a pathogenic mutation but is a functional polymorphism. In the present study, high-throughput screening of serum GLA could successfully indentify two Fabry disease patients in a cohort consisted of 1080 male hemodialysis patients. Moreover, our serum assay was able to distinguish two patients with disease-causing genetic mutations (p.G195V and p.M296I) from eight functional variants that showed relatively decreased enzyme activity (p.E66Q). In conclusion, high-throughput serum enzyme assay distinctly identified disease-causing mutants and functional variants of GLA gene in Japanese male hemodialysis patients. In addition, our results underscore the high prevalence of not only undiagnosed Fabry patients but functional variants of p.E66Q among the ESRD population.
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Acknowledgements
The authors thank Drs Hiromi Shimoyama, Toshimasa Takahashi, Mitsumine Fukui, Hyoe Tomita, Akiko Ogura, Takashi Ozawa, Katsufumi Sakata, Miho Enomoto, Takako Suzuki, Junichiro Mera and Naoto Fujizuka for providing samples. This work was partly supported by Grants from the Japan Society for the Promotion of Science (ID: 23659527 and 21390314, HS and ID: 24390212, EN); the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (ID: 09-15, HS); the Program for Research on Intractable Diseases of Health and Labor Science Research Grants (HS); the JAPS Asia/Africa Scientific Platform Program (HS); and the High-Tech Research Center Project of the Ministry of Education, Culture, Sports, Science and Technology of Japan (ID: S0801043, HS).
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Doi, K., Noiri, E., Ishizu, T. et al. High-throughput screening identified disease-causing mutants and functional variants of α-galactosidase A gene in Japanese male hemodialysis patients. J Hum Genet 57, 575–579 (2012). https://doi.org/10.1038/jhg.2012.68
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DOI: https://doi.org/10.1038/jhg.2012.68
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