Severe myocardial fibrosis caused by a deletion of the 5' end of the lamin A/C gene

J Peter van Tintelen, Rene Tio, Wilhemina Kerstjens-Frederikse, Jop van Berlo, Ludolf Boven, Albert Suurmeijer, Stefan John White, Johan den Dunnen, Gerard te Meerman, Yvonne Vos, Annemarie van der Hout, Jan Osinga, Maarten van den Berg, Dirk Jan van Veldhuisen, Charles Buys, Robert Hofstra, Yigal Pinto

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OBJECTIVES: The goal of this study was to identify the underlying gene defect in a family with inherited myocardial fibrosis. BACKGROUND: A large family with an autosomal dominantly inherited form of myocardial fibrosis with a highly malignant clinical outcome has been investigated. Because myocardial fibrosis preceded the clinical and echocardiographic signs, we consider the disease to be a hereditary form of cardiac fibrosis. METHODS: Twenty-five family members were clinically evaluated, and 5 unaffected and 8 affected family members were included in a genome-wide linkage study. RESULTS: The highest logarithm of the odds (LOD) score (LOD = 2.6) was found in the region of the lamin AC (LMNA) gene. The LMNA mutation analysis, both by denaturing gradient gel electrophoresis and sequencing, failed to show a mutation. Subsequent Southern blotting, complementary deoxyribonucleic acid sequencing, and multiplex ligation-dependent probe amplification analysis, however, revealed a deletion of the start codon-containing exon and an adjacent noncoding exon. In vitro studies demonstrated that the deletion results in the formation of nuclear aggregates of lamin, suggesting that the mutant allele is being transcribed. CONCLUSIONS: This novel LMNA deletion causes a distinct, highly malignant cardiomyopathy with early-onset primary cardiac fibrosis likely due to an effect of the shortened mutant protein, which secondarily leads to arrhythmias and end-stage cardiac failure.
Original languageEnglish
Pages (from-to)2430 - 2439
Number of pages10
JournalJournal of the American College of Cardiology
Issue number25
Publication statusPublished - 2007
Externally publishedYes

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