'Trafficking' Abnormality Underlies Common Form of Type 2 CMT

April 13, 2007

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MDA grantee Baloh at Washington University in St. Louis, with

Alan Pestronk, who directs the MDA clinic at that institution, were

part of a study team that recently unveiled the mechanism by which

mutations in the gene for mitofusin 2 (MFN2) cause Charcot-Marie-

Tooth disease (CMT).

Mutations in the MFN2 gene are estimated to cause 19 percent to 33

percent of cases of type 2 CMT, the type that results from damage to

the nerve fibers (axons) that run between cell bodies in the spinal

cord and the periphery of the body. CMT is characterized by movement

and sensory abnormalities, especially in the hands and feet.

Recently, the location of the MFN2 protein has been pinpointed to an

outer membrane surrounding mitochondria, miniature " organs " that

produce a cell's energy. (Each mitochondrion has its own membranes.)

In lab experiments using nerve cells, Baloh and colleagues found

that mutations in the MFN2 gene cause the mitochondria to form

clumps and to cluster at fiber segments near the spinal cord rather

than distributing themselves throughout the fiber, as they normally

would. They called this a " mitochondrial trafficking abnormality. "

Interestingly, the researchers found that energy production -- the

main business of mitochondria -- remained intact.

" Mitochondria are ... localized in [nerve cells] to sites of high

energy demand, " the investigators say in their Jan. 10 paper in the

Journal of Neuroscience. " Because of the high energy demand at very

distant sites from the cell body, the effective trafficking of

mitochondria is presumed to be critical for proper [nerve cell]

function. ... Given that the peripheral sensory and motor axons are

the longest in the body, it is likely that these are among the most

sensitive to a mitochondrial trafficking insult. "

They say developing a mouse with MFN2 defects will shed further

light on this type of CMT.

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