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CLINICAL RESEARCH: CARDIOMYOPATHY

Severe Myocardial Fibrosis Caused by a Deletion of the 5’ End of the Lamin A/C Gene

J. Peter van Tintelen, MD^_*,_*, Rene A. Tio, MD, PhD, Wilhelmina S. Kerstjens-Frederikse, MD^_*, Jop H. van Berlo, MD, Ludolf G. Boven, BSc^_*, Albert J.H. Suurmeijer, MD, PhD, Stefan J. White, PhD^||, Johan T. den Dunnen, PhD^||, Gerard J. te Meerman, PhD^_*, Yvonne J. Vos, MSc^_*, Annemarie H. van der Hout, PhD^_*, Jan Osinga^_*, Maarten P. van den Berg, MD, PhD, Dirk J. van Veldhuisen, MD, PhD, Charles H.C.M. Buys, PhD^_*, Robert M.W. Hofstra, PhD^_* and Yigal M. Pinto, MD, PhD

^_* Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Department of Cardiology, University Hospital Maastricht, Maastricht, the Netherlands
^|| Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.

Manuscript received April 25, 2006; revised manuscript received February 9, 2007, accepted February 12, 2007.

^_* Reprint requests and correspondence: Dr. J. Peter van Tintelen, Department of Genetics, University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, the Netherlands. (Email: p.van.tintelen{at}medgen.umcg.nl).

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.

Abbreviations and Acronyms   DCM = dilated cardiomyopathy   DGGE = denaturing gradient gel electrophoresis   DNA = deoxyribonucleic acid   EMB = endomyocardial biopsy   IDCM = idiopathic dilated cardiomyopathy   LMNA = lamin AC   MLPA = multiplex ligation-dependent probe amplification   PCR = polymerase chain reaction   RNA = ribonucleic acid

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