Nuclear membrane proteins at heart of muscle disorders

Laminopathies are rare genetic diseases that include several muscular and heart disorders, including Emery–Dreifuss muscular dystrophy (EDMD) and dilated cardiomyopathy. They are caused by mutations in LMNA, a gene that encodes the nuclear envelope proteins lamins A and C.

In a new study published in Nature this week, researchers led by Chin Yee Ho of Cornell University in New York, and including Diana Jaalouk from the American University of Beirut, report that mice cells lacking lamins or with mutant lamins have impaired nucleo-cytoplasmic transport of the transcription factor megakaryoblastic leukaemia 1 (MKL1), a protein important for the development and function of the heart.

The study elucidates how nuclear envelope proteins can impair MKL1 signalling. It also explains the beneficial results of previous studies in which mouse models of laminopathies were treated with inhibitors of intracellular signalling known as MAP kinases, which can improve MKL1 signalling by reducing its transport out of the nucleus.

"These findings provide new clues into the molecular mechanisms for the devastating heart diseases associated with many laminopathies, linking defects in structural function with faulty cell signalling, and presenting a new avenue for therapeutic approaches by targeting impaired MKL1 signaling in these diseases," says Jan Lammerding, the senior author of the report.

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