Durham, N.C. – 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 Elisabeth, 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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