title: Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy.
abstract: 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.
authors.affiliation: 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
authors.forename: Andreas
authors.initials: A
authors.lastname: Perrot
authors.forename: Shwan
authors.initials: S
authors.lastname: Hussein
authors.forename: Volker
authors.initials: V
authors.lastname: Ruppert
authors.forename: Hartmut H J
authors.initials: HH
authors.lastname: Schmidt
authors.forename: Manfred S
authors.initials: MS
authors.lastname: Wehnert
authors.forename: Nguyen Thuy
authors.initials: NT
authors.lastname: Duong
authors.forename: Maximilian G
authors.initials: MG
authors.lastname: Posch
authors.forename: Anna
authors.initials: A
authors.lastname: Panek
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kindermann
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Michalewska-Wludarczyk
authors.forename: Anette
authors.initials: A
authors.lastname: Richter
authors.forename: Bernhard
authors.initials: B
authors.lastname: Maisch
authors.forename: Sabine
authors.initials: S
authors.lastname: Pankuweit
authors.forename: Cemil
authors.initials: C
authors.lastname: Ozcelik
mesh_terms: 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
chemical_list: D017931:DNA Primers; C494847:LMNA protein, human; D034904:Lamin Type A; D004247:DNA