title: Severe myocardial fibrosis caused by a deletion of the 5' end of the lamin A/C gene.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. p.van.tintelen@medgen.umcg.nl
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
authors.forename: Rene A
authors.initials: RA
authors.lastname: Tio
authors.forename: Wilhelmina S
authors.initials: WS
authors.lastname: Kerstjens-Frederikse
authors.forename: Jop H
authors.initials: JH
authors.lastname: van Berlo
authors.forename: Ludolf G
authors.initials: LG
authors.lastname: Boven
authors.forename: Albert J H
authors.initials: AJ
authors.lastname: Suurmeijer
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: White
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: te Meerman
authors.forename: Yvonne J
authors.initials: YJ
authors.lastname: Vos
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: van der Hout
authors.forename: Jan
authors.initials: J
authors.lastname: Osinga
authors.forename: Maarten P
authors.initials: MP
authors.lastname: van den Berg
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.forename: Charles H C M
authors.initials: CH
authors.lastname: Buys
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
mesh_terms: D000328:Adult; D017677:Age Distribution; D001707:Biopsy, Needle; D015139:Blotting, Southern; D004562:Electrocardiography; D004719:Endomyocardial Fibrosis / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011379:Prognosis; D018570:Risk Assessment; D012720:Severity of Illness Index; D017678:Sex Distribution; D015996:Survival Rate
chemical_list: D034904:Lamin Type A