Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns.
Fabry disease is caused by an alpha-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(-11)T>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 + or - 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.
Lee
Beom Hee
BH
Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
Heo
Sun Hee
SH
Kim
Gu-Hwan
GH
Park
Jung-Young
JY
Kim
Woo-Shik
WS
Kang
Duk-Hee
DH
Choe
Kyung Hoon
KH
Kim
Won-Ho
WH
Yang
Song Hyun
SH
Yoo
Han-Wook
HW
D000328:Adult; D000368:Aged; D000818:Animals; D019556:COS Cells; D016022:Case-Control Studies; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D000795:Fabry Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D005787:Gene Frequency; D006801:Humans; D007231:Infant, Newborn; D007723:Korea / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D015997:Neonatal Screening; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
D000519:alpha-Galactosidase