Dynamin 2 (more) - Gene With Broad Role Also Causes Prevalent, Inherited Nerve Disorder

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Medical News Today Feb. 1 2005

Gene With Broad Role Also Causes Prevalent, Inherited Nerve Disorder

A gene that plays many fundamental roles in cells throughout the body has, for

the first time, been implicated in human disease, according to researchers at

the Duke Center for Human Genetics. A defect in the ubiquitous gene dynamin 2

underlies one form of the prevalent, familial nerve disorder, known as

Charcot-Marie-Tooth disease (CMT). The disorder affects approximately 1 in every

2,500 people, making it one of the most common of all hereditary disorders, said

the researchers.

Their findings also reveal a previously unknown link between CMT and a

deficiency of white blood cells, suggesting that defects in dynamin 2 might

underlie both conditions, the researchers reported in the Jan. 30, 2005, issue

of Nature Genetics.

The discovery -- together with earlier findings of genes that can also cause the

genetically heterogeneous and debilitating disease -- is providing new insight

into the nervous system, said first author of the study Stephan Züchner, M.D.,

assistant professor of psychiatry and member of the Duke Center for Human

Genetics. Also, he said, the findings bring a better understanding of the types

of defects that might, in general, lead to peripheral nerve disorders.

" As the function of each new gene comes to light, a picture is emerging about

the gene and protein families that underlie different forms of

Charcot-Marie-Tooth disease and perhaps other nervous system diseases as well, "

Züchner said.

As evidence mounts for the genetic basis of the disorder's different forms,

scientists can begin to develop therapies to specifically target the root causes

of CMT in particular families, added senior author Jeffery Vance, M.D.,

associate director of the Center for Human Genetics and professor of medicine at

Duke.

Hallmarks of CMT include weakening of the muscles of the feet and hands that

spreads gradually 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.

The underlying defect in CMT is muscle atrophy due to a lack of stimulation from

the nerves. That lack of stimulation stems from one of two underlying causes,

which define the two primary forms of the disease: CMT type 1 and 2.

In CMT type 1, the speed of the nerve impulse slows due to degradation of the

protective myelin sheath that normally covers nerve axons, Züchner explained.

Axons are the cable-like extension of the neuron from the cell body in the

spinal cord to the juncture, or synapse, between the nerve ending and muscle.

Demyelinated axons conduct nerve impulses at slower rates than normal, causing

communication to stall.

In contrast, patients with CMT type 2, which results from a breakdown in the

nerve axon itself, exhibit normal, or near normal, nerve impulse speeds. Defects

in multiple genes have been found to underlie CMT types 1 and 2.

In rare cases, family members exhibit a form of the disease with symptoms that

fall somewhere between those normally associated with either CMT type 1 or 2,

Züchner said. Earlier research had linked this " intermediate " form of the

disease to unknown genetic defects at three different chromosomal locations.

To further narrow the search for causes, the Duke team screened three unrelated

families, with intermediate CMT linked to one of those chromosomal regions, for

defects in candidate disease genes. Family members who had the condition all

exhibited unique mutations in the well-studied dynamin 2 gene, they found.

The protein encoded by dynamin 2 modulates several critical cellular processes,

which might explain its effects on the nervous system in people with CMT, Vance

said. For example, the protein plays an important role in the recycling of

chemical nerve messengers, or neurotransmitters, in nerves of the peripheral

nervous system.

The protein is also critical for maintaining the network of " microtubules " that

constitutes the transport system for proteins to different parts of the cell, he

added. Such cellular transport is particularly important in the peripheral

nerves given that neurons must span the distance from the spinal cord to the

feet and hands, Vance said.

Further study revealed that the defects in the dynamin 2 gene all fell in the

region that encodes the same portion of its product protein. Two of the

families, who carried a mutation that altered the same amino acid building block

of the dynamin 2 protein, also shared a deficiency of white blood cells, a

condition not previously linked to CMT, the researchers reported.

To further explore the effect of the mutations, the researchers inserted dynamin

2 with the particular defects into cultured cells. Cells with the mutant dynamin

gene exhibited abnormalities, including disorganization of the microtubule

network and an inability to take up substances through endocytosis. Endocytosis

is a process whereby the cell membrane engulfs materials, forming sacs that are

then internalized by the cell.

" Dynamin 2 represents the third protein causing CMT that contains a domain

related to the fusion of cell membranes, suggesting an exceptional role for

these pathways for CMT and for nervous system diseases in general, " Züchner

said. Züchner, Vance and their colleagues reported last year that the gene

mitofusin 2, which plays a critical role in the fusion and fission of the

cellular powerhouses known as mitochondria, underlies CMT type 2A.

While the study results provide intriguing evidence that defects in microtubule

organization and endocytosis might underlie the symptoms of intermediate CMT,

further examination of the gene's effects will be required given its broad

variety of cellular functions, Vance said. Further work is also required to

discern the role of dynamin 2 in the development or survival of peripheral blood

cells and its connection to CMT.

The researchers predict the finding will also lead scientists to consider

dynamin 2 from a whole different perspective -- opening up new avenues for study

of a gene already in the scientific spotlight.

Collaborators on the study include Maher Noureddine, Sofia Oliviera, Marcy

Speer, Judith Stenger, Margaret Pericak-Vance from the Duke Center for Human

Genetics and their colleagues in Australia and Belgium. The research was

supported by the " Association Belge contre les Maladies Neuromusculaires, " the

Fund for Scientific Research-Flanders, the Interuniversity Attraction Poles

program P5/19 of the Belgian Federal Science Office, the Medical Foundation

Queen beth, the Muscular Dystrophy Association, National Health and Medical

Research Council of Australia, the National Institutes of Health, the Special

Research Fund of the University of Antwerp, the University of Sydney, and

donations from family members and friends of CMT families to the Center for

Human Genetics.

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