Researchers Uncover Molecular Consequences of CMT Type 2 Mutations

Researchers have identified molecular consequences of mutations in the MORC2 gene — one of the genes that may cause Charcot-Marie Tooth (CMT) disease.

The mutations, researchers at the University of Cambridge in the U.K. showed, cause alterations in what is known as epigenetic silencing, which is a mechanism for shutting down gene activity by placing chemical flags on the DNA.

This type of control over gene activity is crucial for normal nerve cell functions. The detailed insights into how the processes fail might allow for future efforts to precisely target CMT disease mechanisms.

The study, “Neuropathic mutations in MORC2 perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms,” was made public through the bioRxiv preprint server, and has not yet been peer-reviewed.

Mutations in the MORC2 gene give rise to the subtype Z of CMT type 2, in which axons — the long neuronal projections that send electric signals — start malfunctioning.

In January 2017, the research team published an article in the journal Nature Genetics, which showed that MORC2 mutations linked to CMT activates a complex called HUSH, which carries out the gene silencing order. Based on this finding, they aimed to further characterize the molecular steps involved in this action.

To do so, they compared biochemical features and tracked the cellular behavior of two MORC2  variants linked to CMT — holding mutations called S87L and R252W. In addition, they included normal MORC2 proteins and a mutation linked to severe spinal muscular atrophy (SMA).

Their earlier studies also demonstrated that chemical energy, in the form of a molecule called ATP, is required for the process. When ATP is broken down, the pair disassembles. The disease-associated mutations are found in the region of MORC2 that breaks down ATP.

They’ve now discovered that ATP allows MORC2 proteins to team up in pairs — an action required to activate HUSH. This activity, they noted, is fine-tuned by the rate at which ATP binds and is broken down in the complex.

They also could see that different mutations impact this action in slightly different ways, all centered around the pairing process. Both CMT mutations accelerated the rate at which ATP was degraded.

While the research is far from providing patients with CMT potential relief, understanding the details of molecular disease processes is a necessary step for the later development of treatments that might correct these abnormalities.