We investigated the prevalence of lamin A/C (LMNA) gene defects in familial and sporadic
dilated cardiomyopathies (DCM) associated with atrioventricular block (AVB) or increased
serum creatine-phosphokinase (sCPK), and the corresponding changes in myocardial and
protein expression.
It has been reported that familial DCM, associated with conduction disturbances or
variable myopathies, is causally linked to LMNA gene defects.
The LMNA gene and myocardial ultrastructural and immunochemical changes were analyzed
in 73 cases of DCM (49 pure, 15 with AVB [seven familial, eight sporadic], 9 with
increased sCPK), four cases of familial AVB and 19 non-DCM heart diseases. The normal
controls included eight heart donor biopsies for tissue studies and 107 subjects for
LMNA gene studies.
Five novel LMNA mutations (K97E, E111X, R190W, E317K, four base pair insertion at
1,713 cDNA) were identified in five cases of familial autosomal dominant DCM with
AVB (5/15: 33%). The LMNA expression of the myocyte nuclei was reduced or absent.
Western blot protein analyses of three hearts with different mutations showed an additional
30-kDa band, suggesting a degrading effect of mutated on wild-type protein. Focal
disruptions, bleb formation and nuclear pore clustering were documented by electron
microscopy of the myocyte nuclear membranes. None of these changes and no mutations
were found in the nine patients with DCM and increased sCPK or in the disease and
normal controls.
The LMNA gene mutations account for 33% of the DCMs with AVB, all familial autosomal
dominant. Increased sCPK in patients with DCM without AVB is not a useful predictor
of LMNA mutation.