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Why GLA   Gene Mutations Matter in Fabry Disease

Fabry disease is caused by mutations in the galactosidase alpha gene (GLA  )1,2

There are more than 1000 known mutations of the GLA gene. No single genotypic anomaly causes Fabry disease.3 Instead, a variety of mutations in the GLA gene can give rise to Fabry disease, such as4:

  • Missense mutations5
    • Compose ~60% of the GLA gene mutations
      known to cause Fabry disease
    • Cause the introduction of an incorrect amino acid
      into a protein through a mutation of a single nucleotide
  • Splicing mutations
  • Small deletions and insertions
  • Large deletions

GLA gene mutations can cause either the absence or the deficiency of functional alpha-Gal A.3,4 In terms of absence, this means that alpha-Gal A is not present, or results in the production of a nonfunctional enzyme.3,4 When functionality is affected, this results in improper protein folding or reduces the stability of alpha-Gal A, often leading to enzyme degradation in the endoplasmic reticulum prior to normal transport to the lysosome.4

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  1. Desnick RJ, Brady R, Barranger J, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003;138(4):338-346.
  2. Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. QJM. 2010;103(9):641-659.
  3. Tuttolomondo A, Simonetta I, Duro G, et al. Inter-familial and intra-familial phenotypic variability in three Sicilian families with Anderson-Fabry disease. Oncotarget. 2017;8(37):61415-61424.
  4. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.
  5. Filoni C, Caciotti A, Carraresi L, et al. Functional studies of new GLA gene mutations leading to conformational Fabry disease. Biochim Biophys Acta. 2010;1802(2):247-252.