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Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease
Eloisa Arbustini1, Andrea Pilotto, Alessandra Repetto
1Molecular Diagnostic Division, IRCCS Policlinico San Matteo, Pavia, Italy. e.arbustini@smatteo.pv.it
Insights
Lamin A/C (LMNA) gene mutations cause 33% of familial dilated cardiomyopathies with atrioventricular block. Increased serum creatine-phosphokinase is not a reliable indicator for LMNA mutations in dilated cardiomyopathy.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Heart Disease
Background:
- Familial dilated cardiomyopathy (DCM) with conduction disturbances is linked to Lamin A/C (LMNA) gene defects.
- LMNA gene mutations are implicated in familial DCM with variable myopathies.
- Understanding LMNA's role is crucial for diagnosing and treating inherited cardiomyopathies.
Purpose of the Study:
- Investigate LMNA gene defects in familial and sporadic DCM associated with atrioventricular block (AVB) or elevated serum creatine-phosphokinase (sCPK).
- Analyze associated changes in myocardial and protein expression.
- Determine the diagnostic utility of sCPK for LMNA mutations in DCM.
Main Methods:
- Analyzed the LMNA gene in 73 DCM cases, 4 familial AVB cases, and 19 non-DCM controls.
- Performed ultrastructural and immunochemical analyses on myocardial tissue.
- Utilized Western blot and electron microscopy to assess protein expression and nuclear membrane changes.
Main Results:
- Identified five novel LMNA mutations in 33% of familial autosomal dominant DCM with AVB cases.
- Observed reduced or absent LMNA expression in myocyte nuclei.
- Detected protein degradation and nuclear membrane abnormalities, including focal disruptions and pore clustering.
Conclusions:
- LMNA gene mutations are responsible for 33% of DCM with AVB, exclusively in familial autosomal dominant forms.
- Elevated sCPK in DCM patients without AVB does not predict LMNA mutations.
- LMNA gene analysis is vital for diagnosing specific subtypes of inherited DCM.
Objectives:
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.
Background:
It has been reported that familial DCM, associated with conduction disturbances or variable myopathies, is causally linked to LMNA gene defects.
Methods:
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.
Results:
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.
Conclusions:
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.