Genetics of muscular dystophy

Various forms of human muscular dystrophy result from mutations in genes encoding proteins of the nuclear envelope. A new paper in the February 15th issue of G&D reveals how.

Ten human hereditary laminopathies, including Emery-Dreifuss muscular dystrophy (EDMD), are associated with mutations in the LMNA gene that codes for the nuclear filament proteins, lamins A and C. Dr. Brain Kennedy and colleagues at the University of Washington have used a mouse model of EDMD to elucidate the mechanism by which altered expression of A-type lamins causes progressive muscular degeneration.

Adult skeletal muscle is derived from satellite stem cells, known as myoblasts, which differentiate into mature skeletal muscle cells. While several different types of proteins are known to be involved in myogenesis, the role of A-type lamins in muscle differentiation has remained unclear. Dr. Kennedy and colleagues used Lmna-deficient cells, as well as siRNA-mediated knock-down of Lmna and emerin (a lamin-associated protein) to study the affect of decreased A-type lamin or emerin expression on myoblast differentiation.

The authors found that decreased expression of A-type lamins or emerin changes the expression levels of proteins involved in myogenesis (MyoD, pRB, desmin and M-cadherin), and reduces myoblast differentiation potential. Furthermore, forced expression of MyoD or desmin in Lmna-deficient myoblasts restores this defect. By identifying key myogeneic differentiation factors that are altered in Lmna-deificient cells, Dr. Kennedy and colleagues provide new mechanistic insight into how LMNA mutations contribute to EDMD.