Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns

Beom Hee Lee, Sun Hee Heo, Gu Hwan Kim, Jung Young Park, Woo Shik Kim, Duk Hee Kang, Kyung Hoon Choe, Won Ho Kim, Song Hyun Yang, Han Wook Yoo

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43 Scopus citations

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 11 TA, 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 (43.83.03% 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.

Original languageEnglish
Pages (from-to)512-517
Number of pages6
JournalJournal of Human Genetics
Volume55
Issue number8
DOIs
StatePublished - Aug 2010

Keywords

  • atypical variant
  • E66Q
  • Fabry disease
  • GLA
  • mutation
  • polymorphism

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