Fabry Mutations PDF Print E-mail

Fabry disease phenotypes fall into three general classifications, depending on the degree of residual enzymatic activity1:
  • the classical or severe phenotypes leads to dysfunction in multiple organ systems (including eyes, skin, heart, kidneys)

Patients with the classical phenotype have nonsense, severe missense, frame-shift, and splicing
mutations that result in no  enzyme protein or mutant enzymes with very low activity (1% of normal).

  • two other milder phenotypes, with some residual enzyme activity, with symptoms restricted to heart and kidneys

All cardiac variants described to date had missense mutations that encoded mutant enzyme proteins or intronic lesions that markedly reduced transcript levels, but resulted in sufficient residual α-Gal A activity (1% to 10% of normal) to modify the phenotype.

Mutations that perturb the structure of the protein α-galactosidase A fall into 3 main categories:

  1. active sites - leading to loss of enzyme activity
  2. perturbations in the hydrophobic core of the protein leading to folding defects - the largest group of Fabry disease mutations
  3. mutations leading to broken disulfide bonds , loss of N-glycosilation sites, and others

Overview of the secondary structure of 1r46 - data courtesy of PDBSum - the display below is the wiring diagram of the enzyme. This representation makes it easy to observe active sites, ligand binding, disulfide bonds, and other topography.

A brief summary of essential sites and key to diagram2:

The active site: The catalytic mechanism of the enzyme is revealed by the location of two aspartic acid residues: D170 and D231.

The N-terminal domain contains the active site, which is located at the C-terminal end of β strands β1 - β2, near the end of the β barrel.

The N-linked carbohydrates are found at the surface of the molecule, away from the location of the of the active site and dimer interface.

N-linked carbohydrates are critical for the correct folding and and trafficking of the molecule in the cell.

See table for some of the reported point and stop, missense and nonsense mutations in the α-GAL gene leading to the development of Fabry disease - try to identify positions on above diagram, for full list of the the 245 point and stop mutations see reference1:





α-GAL Structure Importance Type of Mutation Site
47 W G active site residue Active
51 M K contacts to active site W47 and dimer interface Active
92 D H active site residue Active
93 D G active site residue Active
134 Y S/X active site residue/stop Active
236 W C,L/X buried/stop Buried
250 Q X stop -
264 D V/Y near active site residues Active
396 F [Y]/X Unknown mutation not disease associated/stop Other
409 P A, T, S buried, initiates strand beta 16 Buried
410 T K/A buried; no room for Lys, Ala introduces hole Buried

For a guide to protein codes please check the link: Genetic code, codon, amino acid descriptions at Human Genome Variation Society


Missense or nonsense mutations and deletions or insertions of a small number of base pairs were found in most patients with Fabry disease.

Classification of ~ 500 disease-associated GLA mutations that have been reported in the The Human Gene Mutation Database (2011):

Mutation type Number of mutations
Missense/nonsense 344
Splicing 26
Regulatory 1
Small deletions 69
Small insertions 28
Small indels 8
Gross deletions 14
Gross insertions/duplications 1
Complex rearrangements 3
Repeat variations 0
Public total 494(631)

The extensive database of mutations identified in Fabry disease patients, combined with the three-dimensional structure of the glycoprotein, leads to a unique molecular understanding of the disease. Additionally, the family of lysosomal storage diseases have many similar traits, so better understanding of the molecular defects in Fabry disease will lead to better understanding of the entire family3.

Referencing links:

PDBsum is a pictorial database that provides an at-a-glance overview of the contents of each 3D structure deposited in the Protein Data Bank (PDB).

Structure of 1r46 - in PDBSum - P06280 (AGAL_HUMAN), GLA, Alpha-galactosidase A

The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff - registration required - free for registered users from academic institutions/non-profit organisations.


1. Abigail I. Guce and Scott C. Garman, 'The Structure of α-Galactosidase A and implications for Fabry Disease chapter, 2 in Human Elstein, Deborah; Altarescu, Gheona; Beck, Michael (Eds.), Fabry Disease ~ 1st Edition., 2010, XXXVII, 512 p.,  ISBN 978-90-481-9032-4 [Link]

2. Garman SC, Garboczi DN., The molecular defect leading to Fabry disease: structure of human alpha-galactosidase., J Mol Biol. 2004 Mar 19;337(2):319-35. [PubMed]

3. Abigail I. Guce and Scott C. Garman, The Structure of Human α-Galactosidase A and Implications for Fabry Disease in FABRY DISEASE 2010, Part 1, 21-38, DOI: 10.1007/978-90-481-9033-1_2 [Chapter Link]

Last Updated on Tuesday, 11 June 2013 14:19