Blazing a new path for Emery-Dreifuss Muscular Dystrophy

December 11, 2005

Bushwhacking through the cellular jungle, researchers are always relieved to stumble across a known molecular pathway. Imagine their excitement at finding a major intersection in unmapped territory. Antoine Muchir and Howard Worman at the Columbia University College of Physicians & Surgeons in New York and their colleagues in France, have discovered a cellular "crossroads" that links the function of the MAP kinase pathway, long implicated in heart failure, to A-type nuclear lamins. Mutations in LMNA, the gene encoding all A-type lamins, cause at least two heritable diseases that affect the heart: Dilated Cardiomyopathy with conduction system defects (DC) and Emery-Dreifuss Muscular Dystrophy (EDMD), which affects muscles and tendons in addition to causing life-threatening cardiomyopathy and cardiac conduction system defects. Muchir presented the findings Sunday at the 45th Annual Meeting of the American Society for Cell Biology in San Francisco.

Instead of using a machete, these cellular trailblazers followed a mouse. The researchers created a "knock-in" model mouse by replacing the normal mouse LMNA gene with a mutated human gene that causes EDMD. Lamin proteins form a network of filaments inside the nucleus, conferring shape and mechanical stability, but they are also "used" by many other proteins and pathways in the nucleus, for a variety of purposes. Mutations in LMNA cause a wide range of human diseases--besides DC and EDMD, these "laminopathies" include other heritable forms of muscular dystrophy, lipodystrophy, neuropathy, bone disorders and accelerated aging (progeria) syndromes.

But no one knew why defective A-type lamins, which are expressed in almost all differentiated cells in the body, specifically affected the heart. Muchir and collaborators used their 'knock-in' EDMD model mouse to test the immediate effects of this lamin mutation on gene expression. Taking cardiac muscle from the genetically altered mice, the researchers used "gene chip" DNA microarrays to rapidly screen for changes in expression levels. Unlike normal mouse hearts, the mutant hearts showed increased expression of genes encoding MAP kinases, which were previously implicated in heart hypertrophy and failure. These same experiments also revealed changes in the expression of genes encoding other components of the muscle contraction apparatus, an angiogenesis factor and a heart hormone. All three play roles in other forms of cardiomyopathy.

As for MAP kinases, the laminopathy connection couldn't have turned up a more promising pathway. Short for "mitogen-activated pathway," the MAP kinase family influences many aspects of cell life including gene expression, mitosis, differentiation and apoptosis (programmed cell death). MAP kinases have attracted basic researchers for decades, and pharmaceutical companies have begun developing MAP kinase inhibitors as potential therapeutic agents. The trail blazed here by Muchir and colleagues opens the possibility that MAP kinase inhibitors could be used to treat lamin-related cardiomyopathies.
-end-


American Society for Cell Biology

Related Muscular Dystrophy Articles from Brightsurf:

Using CRISPR to find muscular dystrophy treatments
A study from Boston Children's Hospital used CRISPR-Cas9 to better understand facioscapulohumeral muscular dystrophy (FSHD) and explore potential treatments by systematically deleting every gene in the genome.

Duchenne muscular dystrophy diagnosis improved by simple accelerometers
Testing for Duchenne muscular dystrophy can require specialized equipment, invasive procedures and high expense, but measuring changes in muscle function and identifying compensatory walking gait could lead to earlier detection.

New therapy targets cause of adult-onset muscular dystrophy
The compound designed at Scripps Research, called Cugamycin, works by recognizing toxic RNA repeats and destroying the garbled gene transcript.

Gene therapy cassettes improved for muscular dystrophy
Experimental gene therapy cassettes for Duchenne muscular dystrophy have been modified to deliver better performance.

Discovery points to innovative new way to treat Duchenne muscular dystrophy
Researchers at The Ottawa Hospital and the University of Ottawa have discovered a new way to treat the loss of muscle function caused by Duchenne muscular dystrophy in animal models of the disease.

Extracellular RNA in urine may provide useful biomarkers for muscular dystrophy
Massachusetts General Hospital researchers have found that extracellular RNA in urine may be a source of biomarkers for the two most common forms of muscular dystrophy, noninvasively providing information about whether therapeutic drugs are having the desired effects on a molecular level.

Tamoxifen and raloxifene slow down the progression of muscular dystrophy
Steroids are currently the only available treatment to reduce the repetitive cycles of inflammation and disease progression associated with functional deterioration in patients with muscular dystrophy (MD).

Designed proteins to treat muscular dystrophy
The cell scaffolding holds muscle fibers together and protects them from damage.

Gene-editing alternative corrects Duchenne muscular dystrophy
Using the new gene-editing enzyme CRISPR-Cpf1, researchers at UT Southwestern Medical Center have successfully corrected Duchenne muscular dystrophy in human cells and mice in the lab.

GW researcher finds genetic cause of new type of muscular dystrophy
George Washington University & St. George's University of London research, published in The American Journal of Human Genetics, outlines a newly discovered genetic mutation associated with short stature, muscle weakness, intellectual disability, and cataracts, leading researchers to believe this is a new type of congenital muscular dystrophy.

Read More: Muscular Dystrophy News and Muscular Dystrophy Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.