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GLA gene mutations and inheritance

About Fabry disease

GLA gene mutations and inheritance

To date, there are more than 1000 known mutations of the GLA gene that give rise to Fabry disease. In most patients, a single point mutation is enough to cause disease. However, different mutations cause varying symptoms and severity.1

This graphic shows the different types of GLA mutation which may give rise to the classic and late-onset Fabry phenotypes.

Classic phenotype

  • Caused by GLA mutations that significantly alter α-Gal A so it has little or no activity2
  • Mutations include:3
    1. Large and small gene rearrangements
    2. Splicing defects
    3. Missense or nonsense variants

Late–onset phenotype

  • Caused by GLA mutations that reduce the effectiveness of α-Gal A but result in some residual activity2
  • Mutations include:3
    1. Missense variants
    2. Splicing defects

Examples of known GLA variants

Many of the GLA mutations seen in patients with Fabry disease involve the hydrophobic core of the α-Gal A dimer, not just the active site. This suggests Fabry disease is primarily a condition of abnormal protein folding. This diagram illustrates the location of many of the known mutations. Changes to the active site are coloured red, the core of the enzyme in blue and other changes in yellow. The green ligand indicates the location of the active site.4

Reproduced with permission from Garman SC. 2007.4

Genotype-phenotype correlation

In many cases, it is difficult to make clear links between genotype and phenotype for several reasons

Most pathogenic GLA variants are specific to a single family, and even individuals within the same family show significant variation in symptoms and severity3

The common signs and symptoms of late-onset Fabry (e.g. stroke or cardiomyopathy) can have many other causes. In patients with a GLA mutation, it can be difficult to determine whether these symptoms have been caused by the mutation or another factor3

Some specific pathogenic GLA variants have been found in both people with the classic and later-onset phenotypes, suggesting there are other factors influencing how the condition affects different individuals3

The GLA gene lies on the X-chromosome, making Fabry disease an X-linked condition. As a result, males are more likely to be severely affected than females, as they only have one X-chromosome and one (mutated) GLA gene.2