Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene With Broad Role Also Causes Prevalent, Inherited Nerve Disorder

01.02.2005


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.

Kendall Morgan | EurekAlert!
Further information:
http://www.dukemednews.org
http://www.duke.edu

More articles from Life Sciences:

nachricht Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University

nachricht How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>