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Blazing a new path for Emery-Dreifuss Muscular Dystrophy


News from the Cell Biology Meeting in San Francisco

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.

John Fleischman | EurekAlert!
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