Charcot-Marie-Tooth disease : researchers founds link with the aminoacyl-tRNA synthetases enzyme


Treatments have been hard to pinpoint for a rare neurological disease called Charcot-Marie-Tooth (CMT), in part because so many variations of the condition exist.

So far, mutations on more than 90 genes have been positively linked to the disorder; a patient needs just one of those mutations for the disease to emerge.

Regardless of which genetic mutation is present, CMT universally inflicts damage on patients’ peripheral nervous system, which extends from the spinal cord into the hands and feet.

For that reason, patients often experience difficulties with balance, walking and fine motor skills, such as buttoning a shirt.

“The genetic mutations of CMT are well understood, but the disease-causing mechanisms are still a mystery on a molecular and cellular level,” says Scripps Research Professor Xiang-Lei Yang, PhD, who led the research.

“In our latest study, we took a bottom-up approach, looking for commonalities among different mutations in one of these genes in the hope that we will uncover new insights for treatment.”

In research that appears in the journal PNAS, Yang and her team focused on ubiquitous enzymes known as aminoacyl-tRNA synthetases.

These enzymes are not only Yang’s long-running research specialty, but also the largest protein family linked to CMT disease.

Pervasive throughout the body, these enzymes attach to the appropriate amino acids to kick off the first step of making new proteins.

Considering that proteins are the building blocks of everything from blood and hormones to skin and bones, this process is central to human life.

Yang says that earlier research, which examined the mutated enzymes independent of other biology, had shown that the disease-affected aminoacyl-tRNA synthetases didn’t work as well as their healthy counterparts. In the scientific world, this is known as a “loss of function.”

But using patient samples and viewing the enzymes in their natural cellular environment, Yang’s lab found something different: Any loss of function disappeared when the mutated enzymes were paired with other healthy enzymes that exist within a cell.

The finding makes sense, she says, as CMT would be far more severe if this enzyme’s crucial biological function was amiss.

But if there was no loss of function, how were these mutated enzymes implicated in disease?

That was the next question Yang sought to answer. For this line of inquiry, she looked at shape rather than function.

Using biochemical and biophysical analysis tools, Yang and her team discovered that the mutated enzymes took on an unusual extended shape.

This is unlike their healthy counterparts, which have a more compact design with far less exposed surface.

“The extra surface area may create unwanted interactions with nearby proteins, and these interactions could be what leads to a diseased state,” Yang says.

In fact, further study showed that disease severity is likely linked with the degree to which the enzyme’s shape was relaxed or extended.

Sisters Aimee and Ashlee, 10, are living with a rare and complex neurodegenerative condition known as Charcot-Marie-Tooth disease, which has no cure. Scientists at Scripps Research are investigating the role that misshapen enzymes may play in disease development and severity.

As her next step of research, Yang plans to delve more deeply into the connection between different forms of CMT, which may lead to general strategies for treating the disease. Her motivation, in addition to a scientist’s need for understanding, are CMT patients and their families–many of whom have personally reached out to her.

“One in 2,500 people have CMT, and today there is no therapy available to help them,” Yang says. “We believe the best path to a treatment is to start by understanding what is fundamentally wrong in the biological environment of this complex neurodegenerative disease.”

Authors of the study, “CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells,” are David Blocquel, Litao Sun, Zaneta Matuszek, Sheng Li, Thomas Weber, Bernhard Kuhle, Grace Kooi, Na Wei, Jonathan Baets, Tao Pan, Paul Schimmel, and Xiang-Lei Yang.

Funding: This work was supported by the National Institutes of Health [Grant R01 GM088278] and a fellowship from National Foundation for Cancer Research.

Charcot-Marie-Tooth disease encompasses a group of disorders called hereditary sensory and motor neuropathies that damage the peripheral nerves.

Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves that worsens over time can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.

Charcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood.

Symptoms of Charcot-Marie-Tooth disease vary in severity and age of onset even among members of the same family.

Some people never realize they have the disorder because their symptoms are so mild, but most have a moderate amount of physical disability.

A small percentage of people experience severe weakness or other problems which, in very rare cases, can be life-threatening.

In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.

Typically, the earliest symptoms of Charcot-Marie-Tooth disease result from muscle atrophy in the feet. Affected individuals may have foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes).

They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. As the disease worsens, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.

Affected individuals may also develop weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs.

People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations.

In rare cases, affected individuals have loss of vision or gradual hearing loss that sometimes leads to deafness.

There are several types of Charcot-Marie-Tooth disease, which are differentiated by their effects on nerve cells and patterns of inheritance. Type 1 (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to transmit nerve impulses.

These abnormalities slow the transmission of nerve impulses and can affect the health of the nerve fiber.

Type 2 (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body to muscles or to sense organs.

These abnormalities reduce the strength of the nerve impulse. In forms of Charcot-Marie-Tooth disease classified as intermediate type, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both myelin and axons.

Type 4 (CMT4) is distinguished from the other types by its pattern of inheritance; it can affect either the axons or the myelin.

Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1) indicate different genetic causes.

Sometimes other, historical names are used to refer to particular forms of Charcot-Marie-Tooth disease. For example, Roussy-Levy syndrome is a form of CMT11 with the additional feature of rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease; it is also sometimes called type 3 (CMT3).

Depending on the specific gene that is altered, this severe, early-onset form of the disorder may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome.

Scripps Research Institute
Media Contacts:
Kelly Quigley – Scripps Research Institute
Image Source:
The image is credited to the Martin family.

Original Research: Closed access
“CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells”. David Blocquel, Litao Sun, Zaneta Matuszek, Sheng Li, Thomas Weber, Bernhard Kuhle, Grace Kooi, Na Wei, Jonathan Baets, Tao Pan, Paul Schimmel, and Xiang-Lei Yang.
PNAS doi:10.1073/pnas.1908288116.


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