Finding Your Gene

Researchers have discovered over 120 genes linked to CMT; dozens were found with CMTA funding initiatives. Despite this, referred to as the “diagnostic gap,” more than 50% of all who have CMT Type 2 still aren’t able to obtain genetic confirmation of their disease. Many who fall into this gap have variants of unknown or uncertain significance (VUS).

A VUS is a gene mutation, and scientists haven’t yet figured out if it causes something, like CMT, or if it’s benign and harmless. With CMTA support, in conjunction with the Inherited Neuropathies Consortium (INC), researchers at the University of Miami, led by CMTA Strategy To Accelerate Research (STAR) Board member Stephan Zuchner, MD, PhD, are working to solve these CMT VUS puzzles.

Through expanded data collection and analysis of DNA sequences from almost 2,700 CMT patients in 30 countries and growing, Dr. Zuchner and colleagues are using the GENESIS database and analysis platform to understand what a VUS might mean for the CMT patient, and this sometimes leads to the discovery of a new CMT gene. This critical work has led to the discovery of more than 25 genes in recent years, including the CADM3 (CMT2GG), COQ7 (dHMN-COQ7), ITPR3 (CMT1J), and SORD (CMT-SORD) genes. This program has a goal of collecting DNA sequences from 10,000 CMT patients.

Fixing Your Gene

Everybody usually has two copies of every gene, with very few exceptions. In many types of CMT, such as CMT2A and CMT2E, the gene with the responsible mutation, the MFN2, and the NEFL genes, respectively, each have one copy with a CMT-causing mutation while the second copy is unaffected. Scientists are developing techniques to “edit out” the mutated copy while preserving the normally functioning copy.

With CMTA support, researchers at the Gladstone Institute, led by CMTA-STAR board member Bruce Conklin, MD, have demonstrated with CRISPR/Cas9 that it’s possible to remove (edit out) the copy of the gene with the responsible mutation while leaving the unaffected copy unharmed and functioning normally. This approach resulted in “curing” affected CMT2E neuron cells in the laboratory.

The Gladstone Institute researchers believe this technology can apply to many other types of CMT. They are currently testing this approach and developing ways to deliver the gene editing capability directly to the nerves in a model of CMT2E while refining these techniques to make them as safe and effective as possible.

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Is your type of CMT unknown despite all attempts at genetic testing? If so, CMTA has a research opportunity for you that might lead to finding your gene/type of CMT. Learn more by visiting this link.