Severe myocardial fibrosis caused by a deletion of the 5' end of the lamin A/C gene.
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.
van Tintelen
J Peter
JP
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. p.van.tintelen@medgen.umcg.nl
Tio
Rene A
RA
Kerstjens-Frederikse
Wilhelmina S
WS
van Berlo
Jop H
JH
Boven
Ludolf G
LG
Suurmeijer
Albert J H
AJ
White
Stefan J
SJ
den Dunnen
Johan T
JT
te Meerman
Gerard J
GJ
Vos
Yvonne J
YJ
van der Hout
Annemarie H
AH
Osinga
Jan
J
van den Berg
Maarten P
MP
van Veldhuisen
Dirk J
DJ
Buys
Charles H C M
CH
Hofstra
Robert M W
RM
Pinto
Yigal M
YM
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
D034904:Lamin Type A