A carboxy-terminal truncation of human alpha-galactosidase A in a heterozygous female with Fabry disease and modification of the enzymatic activity by the carboxy-terminal domain. Increased, reduced, or absent enzyme activity depending on number of amino acid residues deleted

J Clin Invest. 1996 Oct 15;98(8):1809-17. doi: 10.1172/JCI118981.


Fabry disease is an X-linked disorder of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A (alpha-Gal A). We identified a novel mutation of alpha-Gal A gene in a family with Fabry disease, which converted a tyrosine at codon 365 to a stop and resulted in a truncation of the carboxy (C) terminus by 65 amino acid (AA) residues. In a heterozygote of this family, although the mutant and normal alleles were equally transcribed in cultured fibroblasts, lymphocyte alpha-Gal A activity was approximately 30% of the normal control and severe clinical symptoms were apparent. COS-1 cells transfected with this mutant cDNA showed a complete loss of its enzymatic activity. Furthermore, those cotransfected with mutant and wildtype cDNAs showed a lower alpha-Gal A activity than those with wild type alone (approximately 30% of wild type alone), which suggested the dominant negative effect of this mutation and implied the importance of the C terminus for its activity. Thus, we generated mutant cDNAs with various deletion of the C terminus, and analyzed. Unexpectedly, alpha-Gal A activity was enhanced by up to sixfold compared with wild-type when from 2 to 10 AA residues were deleted. In contrast, deletion of 12 or more AA acid residues resulted in a complete loss of enzyme activity. Our data suggest that the C-terminal region of alpha-Gal A plays an important role in the regulation of its enzyme activity.

MeSH terms

  • Amino Acid Sequence
  • Cloning, Molecular
  • Fabry Disease / genetics*
  • Fabry Disease / therapy
  • Female
  • Heterozygote
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Polymerase Chain Reaction
  • RNA, Messenger / chemistry
  • Structure-Activity Relationship
  • X Chromosome
  • alpha-Galactosidase / chemistry
  • alpha-Galactosidase / genetics*
  • alpha-Galactosidase / metabolism


  • RNA, Messenger
  • alpha-Galactosidase