Alternative splicing in the alpha-galactosidase A gene: increased exon inclusion results in the Fabry cardiac phenotype

Am J Hum Genet. 2002 Apr;70(4):994-1002. doi: 10.1086/339431. Epub 2002 Feb 4.


Fabry disease is an inborn error of glycosphingolipid catabolism, resulting from deficient activity of lysosomal alpha-galactosidase A (alpha-Gal A). A rare alternative splicing that introduces a 57-nucleotide (nt) intronic sequence to the alpha-Gal A transcript from intron 4 of the gene has been identified. In addition, a novel midintronic base substitution that results in substantially increased alternative splicing has been identified in a patient with Fabry disease who has the cardiac variant phenotype. The sequence of the patient's intron 4 contains a single G-->A transversion at genomic nt 9331 (IVS4+919 G-->A ), located at the minus sign4 position of the 3' end of the intronic insertion (nts 9278--9334 in the genomic sequence). Minigene constructs containing the entire intron 4 sequence with G, A, C, or T at nt 9331 within an alpha-Gal A complementary DNA expression vector were prepared and expressed in COS-1 cells. Whereas transfection of the G or T minigenes transcribed predominantly normal-sized transcripts, the transfection of the A or C minigenes produced a large amount of the alternatively spliced transcript. These results suggest that the G-->A mutation, within an A/C-rich domain, results in increased recognition of the alternative splicing by an A/C-rich enhancer-type exonic splicing enhancer. The intronic mutation was not observed in 100 unrelated unaffected men but was present in 6 unrelated patients with cardiac Fabry disease. Reverse-transcriptase polymerase chain reaction of total RNA of various normal human tissues revealed that the alternatively spliced transcript was present in all of the samples, and especially at a higher ratio in the lung and muscle. The normal transcript was present in the patients' lymphoblasts and resulted in approximately 10% residual enzyme activity, leading to a cardiac phenotype of Fabry disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics*
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • COS Cells
  • Exons / genetics*
  • Fabry Disease / complications
  • Fabry Disease / enzymology
  • Fabry Disease / genetics*
  • Fabry Disease / physiopathology*
  • Heart Diseases / complications
  • Heart Diseases / enzymology
  • Heart Diseases / genetics*
  • Heart Diseases / physiopathology*
  • Humans
  • Molecular Sequence Data
  • Mutation / genetics
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Alignment
  • alpha-Galactosidase / chemistry
  • alpha-Galactosidase / genetics*


  • RNA, Messenger
  • alpha-Galactosidase

Associated data

  • OMIM/MIM301500