Changes at P183 of emerin weaken its protein-protein interactions resulting in X-linked Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive muscular dystrophy characterized by early contractures of the elbows, Achilies tendo ns and spine, slowly progressive muscle wasting and weakness. and cardiomyo pathy associated with cardiac conduction defects. The emerin gene has been mapped to Xq28 and encodes a 34-kDa serine-rich protein, emerin, which has been localized to the nuclear envelope in a wide variety of tissues, includ ing skeletal and cardiac muscle, Mutations spanning the emerin gene have be en identified in patients with EDMD. We present here the effect, on emerin protein expression. of two missense mutations identified in unrelated EDMD patients. These alterations predict the replacement of a proline residue at position 183 with either a histidine or a threonine. Biochemical analysis has demonstrated that the mobility and expression levels of the mutant form s of emerin are indistinguishable from that of wild-type emerin, but that t hey have weakened interactions with nuclear lamina components. In compariso n with the usual EDMD phenotype, patients with P183 missense mutations have a later age at onset of first symptoms, elbow contractures, ankle contract ures, upper limb weakness and lower limb weakness, but there is no differen ce for the age at onset of cardiac involvement. This is the first report of protein studies on patients with missense mutations resulting in the clini cal features of EDMD, These studies demonstrate the importance of proline 1 83 for the proper structure/function of emerin.