Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations.

AIMS: Mutations in the lamin A/C gene (LMNA) have been reported to be involved in dilated cardiomyopathy (DCM) associated with conduction system disease and/or skeletal myopathy. The aim of this study was to perform a mutational analysis of LMNA in a large white population of patients affected by dilated cardiomyopathy with or without associated symptoms. METHODS: We performed screening of the coding sequence of LMNA on DNA samples from 66 index cases, and carried out cell transfection experiments to examine the functional consequences of the mutations identified. RESULTS: A new missense (E161K) mutation was identified in a family with early atrial fibrillation and a previously described (R377H) mutation in another family with a quadriceps myopathy associated with DCM. A new mutation (28insA) leading to a premature stop codon was identified in a family affected by DCM with conduction defects. No mutation in LMNA was found in cases with isolated dilated cardiomyopathy. Functional analyses have identified potential physiopathological mechanisms involving identified mutations, such as haploinsufficiency (28insA) or intermediate filament disorganisation (E161K, R377H). CONCLUSION: For the first time, a specific phenotype characterised by early atrial fibrillation is associated with LMNA mutation. Conversely, mutations in LMNA appear as a rare cause of isolated dilated cardiomyopathy. The variable phenotypes observed in LMNA-DCM might be explained by the variability of functional consequences of LMNA mutations.

Accuracy of European diagnostic criteria for familial hypertrophic cardiomyopathy in a genotyped population.

BACKGROUND: Since the sensitivity of conventional diagnostic criteria for familial hypertrophic cardiomyopathy (HCM) is low, new diagnostic criteria were proposed by a European collaboration. However, their diagnostic value remains unknown. The aim of the study was to evaluate the accuracy of these new criteria, using the genetic status as the criterion of reference. METHODS: We studied 109 genotyped adults (54 genetically affected, 55 unaffected) from 7 families (mutations in 3 genes). Major European echographic criteria were a maximal wall thickness >or=13 mm or >or=15 mm according to the segment involved, or the presence of SAM. Major European ECG criteria were abnormal Q waves, left ventricular hypertrophy, or marked ST-T changes. Combined major/minor European criteria were also evaluated. RESULTS: Sensitivity and specificity of major European criteria (72 and 92%, respectively) were similar to those of major conventional criteria (70 and 94%) and were not improved by combined major/minor European criteria (72 and 90%). When all the minor European criteria were considered, sensitivity increased to 87% but specificity dramatically decreased to 51%. However, one of these minor ECG criteria, deep S V2, was of interest and when added to major European criteria, sensitivity increased to 76% and specificity remained good (90%). CONCLUSIONS: The diagnostic value of new European criteria for HCM was evaluated for the first time. We found that it was not different from that of conventional criteria, with a good specificity but a low sensitivity. Additional criteria should be studied to improve the early identification of HCM.

A new locus for autosomal dominant dilated cardiomyopathy identified on chromosome 6q12-q16.

Dilated cardiomyopathy (DCM) is a heart-muscle disease characterized by ventricular dilatation and impaired heart contraction and is heterogeneous both clinically and genetically. To date, 12 candidate disease loci have been described for autosomal dominant DCM. We report the identification of a new locus on chromosome 6q12-16 in a French family with 9 individuals affected by the pure form of autosomal dominant DCM. This locus was found by using a genomewide search after exclusion of all reported disease loci and genes for DCM. The maximum pairwise LOD score was 3.52 at recombination fraction 0.0 for markers D6S1644 and D6S1694. Haplotype construction delineated a region of 16.4 cM between markers D6S1627 and D6S1716. This locus does not overlap with two other disease loci that have been described in nonpure forms of DCM and have been mapped on 6q23-24 and 6q23. The phospholamban, malic enzyme 1-soluble, and laminin-alpha4 genes were excluded as candidate genes, using single-strand conformation polymorphism or linkage analysis.

Epidemiology of desmin and cardiac actin gene mutations in a european population of dilated cardiomyopathy.

AIMS: Although dilated cardiomyopathy is the most frequent form of cardiomyopathy, its aetiology is still poorly understood. In about 20-30% of cases the disease is familial with a large predominance of autosomal dominant transmission. Ten different chromosomal loci have been described for autosomal dominant forms of dilated cardiomyopathy. Only two genes have been associated with pure forms (without myopathy and/or conduction disorders) of the disease, the cardiac actin and the desmin genes. Our aim was to determine the proportion of dilated cardiomyopathy affected individuals carrying a mutation in one of these two genes. METHODS AND RESULTS: We performed (1) a systematic polymerase chain reaction-SSCP-sequencing screening of the coding sequences of cardiac actin on DNA samples from 43 probands of dilated cardiomyopathy families and 43 sporadic cases; (2) a systematic polymerase chain reaction-SSCP-sequencing screening of the coding sequences of desmin combined with a search for the described missense mutation (Ile451Met) by restriction fragment length polymorphism analysis on DNA samples from 41 probands of dilated cardiomyopathy families and 22 sporadic cases. CONCLUSION: None of the patients presents a mutation in any of these two genes. Consequently, the proportion of European dilated cardiomyopathy affected individuals bearing a mutation in (1) the cardiac actin gene is less than 1.2%, (2) the desmin gene is less than 1.6%.