Mutations in nine genes associated with Charcot-Marie-Tooth disease type 2 (CMT2) generally lead to similar deficits in muscle structure and function, as well as in motor neuron and muscle cell communication, a study in worms suggested.
This work sheds light on the function of each gene associated with CMT2, and on the common and distinct consequences of their mutations.
Notably, tiny worms with mutations in CMT2-related genes may become useful models to better understand the underlying mechanisms of each CMT2 subtype, identify potential therapeutic targets, and evaluate the effectiveness of potential therapies, the researchers said. Models for CMT2 research are quite limited.
Their study, “Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects in Caenorhabditis elegans,” was published in the journal PLOS One.
CMT2, also known as “axonal CMT,” is characterized by the degeneration of axons — nerve fibers that conduct signals to the next nerve or muscle cell — of the peripheral nervous system, which controls movement and sensation in the limbs.
Axonal damage leads to gradual muscle weakness and atrophy (shrinkage), as well as decreased sensation (heat, cold, touch), mostly in the feet, lower legs, hands, and forearms.
CMT2 is currently classified into multiple subtypes, each associated with mutations in a specific gene. Age of onset, progression, and severity of the disease vary both across subtypes and within the same subtype.
Due to its high variability and lack of animal models for all subtypes, the underlying mechanisms of CMT2 remain largely unknown.
Researchers at Monash University, in Australia, analyzed the defects caused by mutations in nine genes associated with CMT2 in Caenorhabditis elegans, a tiny worm commonly used in research.
Each of the nine strains had a loss-of-function mutation in a gene associated with a different CMT2 subtype. A loss-of-function mutation prevents the production of a functional protein by that gene.
The nine subtypes studied and their respective affected genes included CMT2A (MFN2 gene), CMT2C (TRPV4 gene), CMT2F (HSPB1 gene), CMT2M (DNM2 gene), CMT2R (TRIM2 gene), CMT2T (MME gene), and three unclassified subtypes (KIF5A, ATP7A, and HINT1 genes).
Researchers evaluated muscle structure and function, as well as the activity at the neuromuscular junction (NMJ),the site where a motor neuron communicates with a muscle cell.
To date, reports of impaired communication at the NMJ in CMT2 are limited to mouse models of CMT2D.
Results showed that mutations in seven genes — except HINT1 (unclassified subtype) and MME (CMT2T) — resulted in significant and progressive defects in the worms’ ability to swim and crawl, resembling the progressive motor difficulties seen in CMT2 patients.
These locomotion defects were associated with significant structural changes in the worms’ body wall muscles, but not to severe structural changes in motor nerve cells.
Only worms with mutations in the genes DNM2 (CMT2M) and KIF5A (unclassified subtype) showed such structural defects in motor neurons known to regulate movement. Notably, both genes are involved in the trafficking of organelles and vesicles inside cells.
The degeneration of another type of nerve cell involved in the worm’s locomotion, and not present in mammals, may underlie the movement impairments observed in the other CMT2 subtypes, the researchers said.
Further analyses revealed muscle and NJM dysfunction in several CMT2 subtypes. In particular, worms representative of CMT2A, CMT2M, CMT2R, and KIF5A-associated CMT2 showed significant decreases in the activity of motor neurons at the NMJ, impairing their communication with muscle cells.
The team emphasized that such communication changes correlated with locomotion, nerve cell and muscle function defects, suggesting that NMJ activity likely plays a major role in CMT2-associated motor problems.
“Our study reveals novel insights into the functions of the CMT2-related genes, identifies common and diverse sites of defects when the genes are mutated, and paves the way for future studies aimed at defining the precise function of these genes,” the researchers wrote.
“Mutation of the CMT2-associated genes in this study produced [disease features] that could be related to human patients … [which] is an important step forward in the establishment of reliable animal models to understand disease mechanisms,” they added.
They also said that this is especially relevant for CMT2C, CMT2R, CMT2T and the unclassified CMT2 subtypes, for which no animal models exist to date.
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