Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy.
The familial form of dilated cardiomyopathy (DCM) occurs in about 20%-50% of DCM cases. It is a heterogeneous genetic disease: mutations in more than 20 different genes have been shown to cause familial DCM. LMNA, encoding the nuclear membrane protein lamin A/C, is one of the most important disease gene for that disease. Therefore, we analyzed the LMNA gene in a large cohort of 73 patients with familial DCM. Clinical examination (ECG, echocardiography, and catheterization) was followed by genetic characterization of LMNA by direct sequencing. We detected five heterozygous missense mutations (prevalence 7%) in five different families characterized by severe DCM and heart failure with conduction system disease necessitating pacemaker implantation and heart transplantation. Four of these variants clustered in the protein domain coil 1B, which is important for lamin B interaction and lamin A/C dimerization. Although we identified two novel mutations (E203V, K219T) besides three known ones (E161K, R190Q, R644C), it was remarkable that four mutations represent LMNA hot spots. DCM patients with LMNA mutations show a notable homogenous severe phenotype as we could confirm in our study. Testing LMNA in such families seems to be recommended because genotype information in an individual could definitely be useful for the clinician.
Perrot
Andreas
A
Charité-Universitätsmedizin Berlin, Kardiologie am Campus Buch und Virchow-Klinikum, Experimental and Clinical Research Center (ECRC) am Max-Delbrück-Centrum für Molekulare Medizin, Lindenberger Weg 80, Berlin, Germany. andreas.perrot@charite.de
Hussein
Shwan
S
Ruppert
Volker
V
Schmidt
Hartmut H J
HH
Wehnert
Manfred S
MS
Duong
Nguyen Thuy
NT
Posch
Maximilian G
MG
Panek
Anna
A
Dietz
Rainer
R
Kindermann
Ingrid
I
Böhm
Michael
M
Michalewska-Wludarczyk
Aleksandra
A
Richter
Anette
A
Maisch
Bernhard
B
Pankuweit
Sabine
S
Ozcelik
Cemil
C
D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D015331:Cohort Studies; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D005091:Exons; D005260:Female; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008214:Lymphocytes / Q000502:physiology; D008297:Male; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
D017931:DNA Primers; C494847:LMNA protein, human; D034904:Lamin Type A; D004247:DNA