Various publications attempt to prove the apathogenicity of the controversial mutations. Some of them describe rather individual cases and are therefore not statistically reliable. Others refer to previous publications when making their statements. If you now look at the sources where the original statements with evidence come from, you will very often find two studies from 2003:
- Yasuda: “Fabry disease: characterisation of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele”.
- Froissart: “Fabry disease: D313Y is an alpha-galactosidase A sequence variant that causes pseudodeficient activity in plasma”.
Both authors worked closely together, i.e. the studies are not independent! The studies show altered biochemical and physical properties of the modified enzyme. However, they then assume that these changes have no effect on the cellular level. But already in this study, disturbed processes in the cells are detected, which were later further investigated in studies on another controversial mutation. There it was shown that these changes lead to so-called ER stress (ER = endoplasmic reticulum). This ER stress is the cause of cell malfunction and even cell death. (see also Unfolded Protein Response)
Another point is the so-called ER stress, more about this in our blog entry:
Fabry as a lysosomal storage disease, is there possibly more to it.
(Source e.g. https://doi.org/10.1101/2022.09.27.509714)
I.e. the statements on apathogenicity are often not reliable or even wrong.
Therefore, most authors add that due to the small number of cases and various open questions, apathogenicity cannot necessarily be proven and further research is necessary.
Important Research that is made impossible by the deliberate filtering out of the controversial mutations in the gene laboratory.
A publication from 2020 also refers to these two studies to prove apathogenicity.
In this publication (“An expert consensus document on the management of cardiovascular manifestations of Fabry disease”, Linhart et al. 2020) it was written: “As a cautionary example, the p.Asp313Tyr change results in a serum pseudodeficiency of AGAL-A activity and is not disease-causing. Similarly, a number of GLA variants previously thought to be disease-causing (e.g. p.Arg118Cys) have been shown to be of uncertain significance or likely benign. “(This is followed by a citation)
We have traced back the sources until we reached the original source:
In turn, the Varsome database cites Yasuda’s study as a source to prove pathogenicity.