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Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease
P M Jakobs1, E L Hanson, K A Crispell
1Department of Medicine, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201, USA.
Insights
Novel mutations in the LMNA gene cause familial dilated cardiomyopathy and conduction system disease. These genetic changes in lamin A/C lead to heart conditions without affecting skeletal muscles.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- The LMNA gene encodes lamins A and C, nuclear envelope proteins.
- Mutations in LMNA are linked to various diseases, including dilated cardiomyopathy.
- Familial dilated cardiomyopathy (FDC) is often associated with genetic factors.
Purpose of the Study:
- Investigate novel mutations in the LMNA gene.
- Determine the association between LMNA mutations and familial dilated cardiomyopathy with conduction system disease.
- Characterize the clinical manifestations of these mutations.
Main Methods:
- Genetic analysis of two large families with autosomal dominant FDC and conduction disease.
- Identification and characterization of mutations in the rod segment of lamin A/C.
- Clinical evaluation of affected individuals, including age of onset and disease progression.
Main Results:
- Identified two novel LMNA mutations: a missense mutation (E203K) in Family A and a nonsense mutation (R225X) in Family B.
- Both mutations led to progressive conduction system disease, with varying onset and severity.
- Family B exhibited earlier onset, ventricular arrhythmias, left ventricular enlargement, and systolic dysfunction.
- Heart failure was the cause of death in both families; sudden cardiac death occurred in Family B.
- No skeletal muscle disease was observed in either family.
Conclusions:
- Novel mutations in the rod segment of lamin A/C are a cause of familial dilated cardiomyopathy and conduction system disease.
- These mutations result in variable clinical presentations without associated skeletal myopathy.
- LMNA gene mutations represent a significant genetic factor in FDC.
Background:
The LMNA gene, one of 6 autosomal disease genes implicated in familial dilated cardiomyopathy, encodes lamins A and C, alternatively spliced nuclear envelope proteins. Mutations in lamin A/C cause 4 diseases: Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy type 1B, Dunnigan-type familial partial lipodystrophy, and dilated cardiomyopathy.
Methods And Results:
Two 4-generation white families with autosomal dominant familial dilated cardiomyopathy and conduction system disease were found to have novel mutations in the rod segment of lamin A/C. In family A a missense mutation (nucleotide G607A, amino acid E203K) was identified in 14 adult subjects; disease was manifest as progressive conduction disease in the fourth and fifth decades. Death was caused by heart failure. In family B a nonsense mutation (nucleotide C673T, amino acid R225X) was identified in 10 adult subjects; disease was also manifest as progressive conduction disease but with earlier onset (third and fourth decades), ventricular dysrhythmias, left ventricular enlargement, and systolic dysfunction. Death was caused by heart failure and sudden cardiac death. Skeletal muscle disease was not observed in either family.
Conclusions:
Novel rod segment mutations in lamin A/C cause variable conduction system disease and dilated cardiomyopathy without skeletal myopathy.
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