Fabry disease: biochemical, pathological and structural studies of the α-galactosidase A with E66Q amino acid substitution

Mol Genet Metab. 2012 Apr;105(4):615-20. doi: 10.1016/j.ymgme.2012.01.010. Epub 2012 Jan 18.


Recently, male subjects harboring the c.196G>C nucleotide change which leads to the E66Q enzyme having low α-galactosidase A (GLA) activity have been identified at an unexpectedly high frequency on Japanese and Korean screening for Fabry disease involving dry blood spots and plasma/serum samples. Individuals with the E66Q enzyme have been suspected to have the later-onset Fabry disease phenotype leading to renal and cardiac disease. However, there has been no convincing evidence for this. To determine whether c.196G>C (E66Q) is disease-causing or not, we performed biochemical, pathological and structural studies. It was predicted that the E66Q amino acid substitution causes a small conformational change on the molecular surface of GLA, which leads to instability of the enzyme protein. However, biochemical studies revealed that subjects harboring the E66Q enzyme exhibited relatively high residual enzyme activity in white blood cells, and that there was no accumulation of globotriaosylceramide in cultured fibroblasts or an increased level of plasma globotriaosylsphingosine in these subjects. An electron microscopic examination did not reveal any pathological changes specific to Fabry disease in biopsied skin tissues from a male subject with the E66Q enzyme. These results strongly suggest that the c.196G>C is not a pathogenic mutation but is a functional polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amino Acid Substitution
  • Asian People
  • Cells, Cultured
  • Child, Preschool
  • DNA Mutational Analysis
  • Fabry Disease / enzymology*
  • Fabry Disease / genetics*
  • Fabry Disease / pathology
  • Fibroblasts / cytology
  • Fibroblasts / enzymology
  • Heterozygote
  • Humans
  • Immunoblotting
  • Male
  • Microscopy, Electron
  • Middle Aged
  • Models, Molecular
  • Mutation / genetics*
  • Phenotype
  • Real-Time Polymerase Chain Reaction
  • Skin / cytology
  • Skin / enzymology
  • Trihexosylceramides / blood
  • alpha-Galactosidase / chemistry
  • alpha-Galactosidase / genetics*
  • alpha-Galactosidase / metabolism*


  • Trihexosylceramides
  • globotriaosylceramide
  • alpha-Galactosidase