High-throughput screening identified disease-causing mutants and functional variants of α-galactosidase A gene in Japanese male hemodialysis patients.
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.
Department of Nephrology and Endocrinology, University Hospital, The University of Tokyo, Tokyo, Japan.
Kent
K
Doi
Eisei
E
Noiri
Tomoko
T
Ishizu
Kousuke
K
Negishi
Yoshifumi
Y
Suzuki
Yoshifumi
Y
Hamasaki
Kenjiro
K
Honda
Toshiro
T
Fujita
Takahiro
T
Tsukimura
Tadayasu
T
Togawa
Seiji
S
Saito
Hitoshi
H
Sakuraba
D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D004796:Clinical Enzyme Tests / Q000379:methods*; D000795:Fabry Disease / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D005838:Genotype; D057166:High-Throughput Screening Assays; D006801:Humans; D007564:Japan; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D006435:Renal Dialysis; D000519:alpha-Galactosidase / Q000097:blood / Q000235:genetics*
D000519:alpha-Galactosidase