Mutation May Cause Inherited Neuropathy (CMT)

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Mutation May Cause Inherited Neuropathy

http://www.newswise.com/articles/view/536402/

Mutations in a protein called dynein, required for the proper

functioning of sensory nerve cells, can cause defects in mice that

may provide crucial clues leading to better treatments for a human

nerve disorder known as peripheral neuropathy, which affects about

three percent of all those over age 60.

Peripheral neuropathy results from damage to the nerves and nerve

processes that are located outside the brain and spinal cord.

Symptoms include pain in the hands and arms, legs and feet--

sometimes constant and quite severe--as well as progressive numbness

and weakness in the arms and legs. Despite its prevalence, little is

known about the precise causes of the disease or how to prevent or

treat it.

In the December 26, 2007, issue of the Journal of Neuroscience,

however, researchers at the University of Chicago Medical Center

show that mice with mutations in only one copy of a gene coding for

one part of dynein protein have severe defects in proprioception,

the ability to perceive the spatial orientation of body parts.

These defects caused a significant reduction in the number of

sensory nerve cells in affected mice. They also caused early-onset

locomotion problems in the mice's hind legs, a defect that appears

to be quite similar to some human neuropathies.

" This gene codes for part of a multi-protein complex, " said study

author Popko, PhD, Jack Professor in Neurological

Diseases at the University of Chicago Medical Center. " So a mutation

in any of these proteins, or disruption in the function of this

multi-protein complex through some other mechanism, could also lead

to very similar abnormalities " in human patients with sensory

neuropathies.

Mutations in the gene for dynein heavy chain 1, Dync1h, led to

movement defects in the hind legs of mice. These defect resembled

human neuropathies, said Popko, particularly some forms of Charcot-

Marie-Tooth disease and hereditary sensory neuropathy.

Charcot-Marie-Tooth disease is one of the most common inherited

neurological disorders, affecting approximately 1 in 2,500 people in

the United States. It is characterized by loss of muscle tissue and

touch sensation, predominantly in the feet and legs. In CMT, both

the sensory nerves that carry signals from receptors in the

extremities to the brain and spinal cord, as well as motor nerves

that relay signals from the brain and spinal cord to the limbs and

internal organs are affected.

Hereditary sensory neuropathy affects predominantly sensory nerves.

Symptoms included sensation loss, decreased or absent reflexes, foot

deformities and various anatomic features.

Dynein appears to be a likely suspect, the authors report. Although

it is found throughout the body, Dynein plays an important role in

the transport of cargo within axons, the elongated extension of

nerve cells that transmit signals from one neuron to another. Dynein

is crucial for survival, because mice that lack dynein or have

mutations in both Dync1h copies die before birth.

Although dynein is important for the whole body, defects are found

only in sensory neurons, and predominantly in hind limbs.

" The key question is why? " said Popko. " This mutation may affect

transport proteins in all neurons, but perhaps the region that is

mutated is more important for the proteins that it transports in

sensory neurons, whereas other regions could play a role in motor

neurons. Also, mutations in different regions of this protein seem

to have different effects. That may be due to differences in the

cargo-binding domains. "

Affected neurons in mice and in patients with sensory neuropathies

have very long axons. Such neurons that transmit signals over huge

distances depend on dynein, the " cargo-transporter " to carry

molecules from the tip of the axon to the neuron's cell bodies. If

the cargo-transporter is somehow disturbed, Popko said, like in the

case of mutations in Dync1h gene, neurons that transmit signals

over " long distances " will suffer more.

" It's very common for neuropathies to affect neurons with the longer

axons, for example those that innervate the legs and feet, " says

Popko. It has been previously suggested that hereditary sensory

neuropathy might be connected with disabled trafficking along the

axons. There have been mutations found in two genes that form a

complex essential for survival of sensory neurons, and this complex

is thought to be transported along the neurons by dynein.

" This study lays the groundwork for the search for disruptions of

this cargo transporting complex in human patients with sensory

neuropathy " , write the authors in their paper.

They are already looking at human patients for similar mutations.

And they're working further on answering new questions, including:

what are the binding partners of dynein that are disrupted in

diseases, and why does this affect sensory and not motor neurons?

This work was supported in part by a grant from the Miriam and

Sheldon Adelson Program in Neural Repair and Rehabilitation.

Additional authors of the paper include Xiang-Jun Chen, Eleni N.

Levedakou, Kathleen J. Millen, L. Wollmann and Betty Soliven

of the University of Chicago.