More on Type 2A Mitochondria research

[Guest guest]

From Duke University:

Genetic basis of hereditary nerve disorder revealed

A major form of one of the most prevalent inherited neurological

disorders in humans, Charcot-Marie-Tooth disease (CMT), stems from an

abnormality in the cellular powerhouses, or mitochondria, that fuel the

nerves required for muscle control, suggests new findings by

neurogeneticists at the Duke Center for Human Genetics and their

international colleagues. The unexpected discovery could open new

research pathways to understanding an array of diseases of the

peripheral nervous system, as well as treatments for CMT, the

researchers said.

In seven families with a form of the degenerative nerve disorder CMT

type 2A, the team discovered that defects in a gene critical to

mitochondrial movement, known as mitofusin 2, underlies the disease

symptoms. Restoring the lost gene function through gene therapy

might ultimately serve as an effective treatment for the disorder, which

currently has no cure, the researchers reported in the April 4, 2004,

issue of Nature Genetics.

CMT affects people of all races, including 150,000 Americans. Hallmarks

of CMT include weakening of the feet and hands that gradually extends to

the legs and arms. The only treatments now available to patients with

the disease include physical therapy and

moderate activity to maintain muscle strength. Patients often rely on

leg braces and, in some cases, become wheelchair-dependent.

While defects in multiple genes are known to underlie various forms of

CMT, the current finding uncovers a whole new mechanism of action that

can cause disease by damaging mitochondria, said lead author of the

study Stephan Züchner, M.D., of the Duke Center for Human Genetics and

the department of neuropathology at the University Hospital Aachen in

Germany.

" Mitochondria must link into constantly shifting networks through fusion

and fission in order to provide the energy required for neurons to fire

and stimulate muscles to move, " said Züchner. " Mitofusin 2 is critical

to that process. "

Two primary forms of CMT are recognized. CMT type 2 is characterized by

a breakdown in the nerve axon -- the cable-like extension of the neuron

from the cell body in the spinal cord to the juncture, or synapse,

between the nerve and the muscle it controls. In contrast, the

demyelinating form of the disease, CMT type 1, results from degradation

of the insulation, called myelin, which covers the nerve axon. Without

the protective myelin, the speed of the nerve impulse slows. In both

types of CMT, muscles atrophy due to a lack of stimulation from the

nerves.

" Our results indicate that mitofusin 2 is a major gene underlying CMT

type 2A, and probably one of the major genes that cause all hereditary

forms of the axonal neuropathy, CMT type 2, " added senior author Jeffery

Vance, M.D., associate director of the Center for Human Genetics and

professor of medicine at Duke. " This marks the

first time that mitochondrial fusion has been implicated in a human

disease and opens up a whole new area of exploration for the basis of

peripheral neuropathies in general. "

Several years ago researchers at the Duke Center for Human Genetics led

by Vance linked the gene responsible for CMT type 2A to chromosome 1.

However, Vance said, the small region of the human genome containing

this gene proved difficult to study because the

sequencing of chromosome 1 was incomplete at that time.

In the current study, the researchers narrowed the chromosomal segment

to a single gene by sequencing that genetic region in seven families

with CMT type 2A having diverse ethnic backgrounds. In each family,

individuals with CMT showed mutations in the gene sequence encoding the

mitochondrial fusion gene, while unaffected family members and healthy

non-relatives did not, reported the researchers. Further analysis of a

pre-existing set of 36 small families with CMT type 2 found that 20

percent of those also carried mutations in mitofusin 2.

Other investigators have found that mouse cells lacking a working copy

of the mitofusin 2 gene can be " rescued " by re-inserting a normal gene

copy, the investigators noted. The finding suggests that CMT symptoms

might be alleviated with gene therapy in patients with the type 2A form,

they added.

Other collaborators include J. Schröder, of the University

Hospital Aachen, along with researchers from Russia, Italy, Belgium,

Turkey and Japan.