Research Updates November-December 2006

Article Highlights:

News on ongoing research projects as of October 2006

by Margaret Wahl on November 1, 2006 - 2:24pm

QUEST Vol. 13, No. 6

Items in this article report on new developments in: myotonic muscular dystrophy, spinal muscular atrophy, Friedreich's ataxia, nemaline myopathy and centronuclear myopathy

New SMA gene mapped

Researchers in France have identified a new genetic form of spinal muscular atrophy (SMA), a disease in which motor neurons (nerve cells) in the spinal cord and sometimes the brainstem degenerate.

Most cases of SMA are due to the inheritance of mutations in each of a child’s two (one from each parent) chromosome 5 genes that instruct for the SMN protein. Another recessive (requiring genetic flaws from both parents) form of SMA, with respiratory failure occurring in the first weeks of life, results from mutations in a gene on chromosome 11. But some people with SMA remain without a genetic diagnosis.

Now, Isabelle Maystadt at Hopital Necker Enfants Malades in Paris, and colleagues, have localized a region on chromosome 1 as containing the gene that, when mutated, can cause another recessive form of SMA. Discovered by studying a large family originating from Mali (near Algeria), this form looks similar to the familiar SMA type 3, but it’s more severe and involves the breathing muscles and muscles of the hands and feet.

The investigators, who published their findings in the July 11 issue of Neurology, are trying to identify the specific gene involved, which should allow more patients to obtain a specific diagnosis. In addition, they say, “Identification of a new gene will, it is hoped, contribute to a better understanding of the molecular mechanisms involved in motor neuron degeneration.”

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Compound reverses gene flaw in cells with Friedreich's ataxia

Investigators at the Scripps Research Institute in La Jolla, Calif., and the University of California-Los Angeles have identified a compound that can reverse the effects of the most common genetic defect underlying Friedreich’s ataxia (FA).

David Herman and colleagues, whose results were published online Aug. 20 in Nature Chemical Biology, used an HDAC (histone deacetylase) inhibitor molecule to reverse the “silencing” of the gene for frataxin that occurs in FA-affected cells.

The silencing is thought to occur because of GAA repeat DNA present on chromosome 9, which underlies this recessively inherited disease in most people who have it. The GAA repeats cause a structural change in the chromosome and alter the way the DNA is packaged in the region of the frataxin gene, keeping it from being recognized by the cell and used to make frataxin protein.

An HDAC inhibitor dubbed 4b blocked this disease-causing effect, apparently exposing the frataxin gene to the cell’s gene-reading mechanisms and allowing it to make frataxin RNA and protein.

The researchers conducted a series of experiments on white blood cells taken from FA patients and carriers, which they grew in laboratory dishes and directly exposed to HDAC inhibitors.

When the cells from FA patients were exposed to HDAC inhibitor 4b, their frataxin RNA levels increased to at least the levels seen in FA carriers (who generally don’t have disease symptoms). Frataxin RNA levels in 4b-treated carriers nearly doubled. The investigators also determined that the cells could produce frataxin protein from the new frataxin RNA.

“The next steps are to see whether the molecules act as histone deacetylase inhibitors in animals, whether the molecules increase frataxin messenger RNA and protein in a mouse model for the disease, and whether the molecules are nontoxic to animals,” said study team member Joel Gottesfeld, a professor of molecular biology at Scripps. “Each of these steps must yield positive results for these molecules to be considered true clinical candidates for FA. Although our results are very encouraging, it will be many months before we know the answers to these important questions.”

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Scientists determine effects of nemaline myopathy mutation

MDA research grantee Alan Beggs, at Children’s Hospital in Boston, was among scientists who recently uncovered some of the consequences of a genetic mutation that causes nemaline myopathy.

Despina Sanoudou and colleagues, who published their findings in the Sept. 1 issue of Human Molecular Genetics, bred mice with a mutation in the alphatropomyosin gene, which is one of the causes of human nemaline myopathy. They found the downstream consequences of this mutation are a pattern of muscle fiber degeneration and regeneration, and a failure of the diaphragm muscle fibers to mature properly.

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Finding may add new cause of centronuclear myopathy

Mice bred without genes for the protein gamma-actin develop a muscle disease that in some respects resembles human centronuclear myopathy (CNM), a disorder characterized by weakness and misplacement of cell nuclei toward the center of the fiber, say researchers at the University of Wisconsin and the University of Maryland.

Researchers coordinated by MDA grantee James Ervasti, now at the University of Minnesota-Twin Cities (although he performed this work while at the University of Wisconsin-Madison), published their results in the September issue of Developmental Cell.

The findings may add to the diversity of genetic mutations and protein abnormalities that underlie CNM, which, until recently, was considered synonymous with myotubular myopathy (MTM). It was so named in the 1960s because the muscle fibers’ appearance superficially resembles that of immature fibers called myotubes.

In 1997, mutations in the gene for myotubularin, on the X chromosome, were identified as the underlying problem in MTM, now generally thought of as a severe form of CNM.

Last year, a team that included Alan Beggs, an MDA research grantee at Children’s Hospital in Boston, identified mutations in the gene for dynamin 2, on chromosome 19, as a cause of dominantly inherited CNM. This form of the disease is generally milder than the X-linked, myotubularin-related form.

In humans, the gamma-actin gene is located on chromosome 17. So far, no patients with gamma-actin-related CNM have been identified. But Ervasti and colleagues write that their findings “support the screening of genetically undiagnosed patients for [gamma-actin] mutations.”

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