New Mutation Identified in Severe Form of Charcot-Marie-Tooth Disease

A new mutation that caused Charcot-Marie-Tooth disease type 4J (CMT4J) — a severe form of the condition — has been described by researchers at McGill University in Canada.

The mutation was found to cause abnormal processing of cell vesicles and cells surface proteins, insights that may advance efforts to slow disease progression in patients with this condition.

Researchers have earlier noted that mutations in the FIG4 gene cause a recessive form Charcot-Marie-Tooth disease. But the study, “A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic Cascade,” found a mutation in the gene not detailed up until now.

The report, published in the Journal of Neuropathology & Experimental Neurology, describes the new mutation in a 48-year-old man diagnosed with Charcot-Marie-Tooth disease at age 13.

The man was wheelchair-bound because of a demyelinating neuropathy (nerve disease with a loss of myelin, the protective layer surrounding neurons, or nerve cells) and severe loss of axons — the long neuronal processes sending signals out to other neurons. Genetic tests revealed that he had two different mutations in his FIG4 gene.

One had been described earlier. The other — a mutation in a so-called intron part of the gene —  appeared to cause lower levels of the FIG4 protein. Introns do not hold protein-coding information, but are crucial for the process of translating a gene into a protein.

This mutation caused what researchers call a splicing defect, which is a fault in how the genetic material is cut and pasted together again to form a mature protein.

Researchers know that FIG4 is involved in cell vesicle processing, so it was not surprising that the patient’s cells held multiple large vacuoles. These storage bubbles are normally found in cells, but were more prominent in the diseased cells. The vesical cell structures were also abnormally dispersed, the researchers said.

But scientists also believe that FIG4 is important for the turnover of membrane proteins. They found further evidence of this in the unusually high levels of a protein called TRPV4 in the membrane of cells taken from the patient.

A set of experiments using lab-grown neurons from mice were also conducted to verify the importance of FIG4 . When the research team eliminated the gene, the motor neurons grew large vacuoles, just as those seen in patients. They also died sooner than control nerve cells.

When researchers blocked the activity of TRPV4, the cells survived for longer, but the inhibition did not reverse the abnormalities in vesicle formation, suggesting that TRPV4 mediates some, but not all, of the disease’s mechanisms.