CMT Test in a Dish
TIN has sponsored the laboratory of Mario Bortolozzi at the Veneto Institute of Molecular Medicine in a research project aimed at creating a “test in a dish for CMT1X”.
This work aims to directly link genetic defects of CMT1X patients, with dysfunction of the protein that is produced by the disease gene, in a manner that can be measured in a single cell.
CMT1X is caused by the inheritance of a gene (gjb1) that has errors in the instructions it carries to guide the production of a protein called Connexin-32. A normal Connexin-32 protein is located at the surface of a Schwann cell, and acts as a portal into the cell, gating the entry and exit of molecules required for cellular function. In many CMT1X patients, Connexin-32 is present at the cell surface, but is defective in its ability to normally open or close the “gate” that it forms there.
The Bortolozzi laboratory has now shown that it can insert the normal (gjb1) gene as well as the different (mutant) forms of it that patients carry, directly into a cell. The lab can then record the activity of the Connexin-32 “gate” as it opens and closes. This test is being used by the laboratory to show how the different patient variants are similar, or differ, in how they affect the normal function of a Schwann cell.
Going forward, the lab will be able to use this test to evaluate potential therapeutic approaches to treat CMT1X, and even to quickly determine whether a patient is likely to respond to treatment.
In an exciting effort in parallel to this work, the Bortolozzi lab has co-authored a publication that shows, for the first time, the detailed structure of the Connexin-32 protein in direct comparison with that of the protein when it bears a patient mutation. Studies in a dish confirm the effect of the mutation on Connexin-32 function.
This sophisticated comparison of Connexin-32 structure and its function in the disease state is being expanded to multiple patient mutations. Computer simulations are being designed that are intended to aid in rapid drug design aimed at returning the diseased gate back to the state required for it to function normally again.
You can find a list of Bortolozzi lab reports resulting from TIN-sponsored research here:
Bortolozzi Lab: Publications related to the TIN-Sponsored project (2023-2024)
You can download the collaborative study of the Connexin-32 protein structure here: