Structures of the lamin A/C R335W and E347K mutants: Implications for dilated cardiolaminopathies

Dilated cardiomyopathy (DCM) is a condition whereby the normal muscular function of the myocardium is altered by specific or multiple aetiologies. About 25–35% of DCM patients show familial forms of the disease, with most mutations affecting genes encoding cytoskeletal proteins. Most of the DCM-related mutations fall in the Lamin AC gene, in particular in the Coil2B domain of the encoded protein. In this context, we focussed our studies on the crystal structures of two lamin Coil2B domain mutants (R335W and E347K). Both R335 and E347 are higly conserved residues whose substitution has little effects on the Coil2B domain three-dimensional structure; we can thus hypothesize that the mutations may interfere with the binding of components within the nuclear lamina, or of nuclear factors, that have been proposed to interact/associate with lamin A/C.

► Defects in the Lamin AC gene have been linked to more than 10 laminopathies.
► R335 and E347 are highly conserved residues, whose mutation preserves Coil2B 3D structure.
► R335W and E347K mutations may affect LMNA interaction with proteins of nuclear lamina.