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Targeted next-generation sequencing detects novel gene-phenotype associations and expands the mutational spectrum in cardiomyopathie

ABSTRACT: Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium,including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), andarrhythmogenic right ventricular cardiomyopathy (ARVC), with higher morbidity andmortality. These diseases are genetically diverse and associated with rare mutations ina large number of genes, many of which overlap among the phenotypes. To betterinvestigate the genetic overlap between these three phenotypes and to identify newgenotype-phenotype correlations, we designed a custom gene panel consisting of 115genes known to be associated with cardiomyopathic phenotypes and channelopathies.A cohort of 38 unrelated patients, 16 affected by DCM, 14 by HCM and 8 by ARVC,was recruited for the study on the basis of more severe phenotypes and family historyof cardiomyopathy and/or sudden death.

PROVIDER: EGAS00001002506 | EGA |

REPOSITORIES: EGA

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Project description:Lamin A/C proteins, encoded by the LMNA gene, are intermediate filament proteins of the nuclear lamina, and predominantly expressed in differentiated cells including cardiomyocytes. Mutations in LMNA are associated with laminopathies, congenital diseases affecting muscle and homeostasis. One of the laminopathies associated with a missense mutation (N195K) in the A-type lamins results in dilated cardiomyopathy (DCM) with arrhythmias and sudden death. However it is unknown how the mutation in this LMNA gene contributes to the mechanism of arrhythmia and sudden death. To investigate this a mouse line expressing the Lmna-N195K (LmnaN195K/N195K) was used. Mutant mice demonstrated reduced fractional shortening, LV mass, wall thickness and dilated cardiomyopathy by echocardiography at 6 weeks consistent with human DCM, and died at an early age (6-7 weeks). Comparative cDNA microarray analysis from LmnaN195K/N195K and the wild type (WT) control ventricles at 6 weeks age revealed significant alterations in the expression of ion channels, transporter proteins, caveolins and associated proteins such as MAP kinases. Transmission electron microscopy analysis showed structural alterations of the ventricular myocytes with increase in number of caveolae. Quantitative Western blot analysis confirmed reduced expression for Cavβ (2 fold) subunits of the L-type Ca2+ channel. In contrast the expression levels of Cav3 (2.5 fold) was significantly increased. To investigate the functional impact of Lmna N195K on the ICa,L, we transiently expressed either the WT LMNA+GFP, Lmna N195K+GFP or GFP (control) in isolated neonatal mouse ventricular myocytes and performed whole cell patch clamp analysis. Transient expression of Lmna N195K significantly reduced (58 %) peak ICa,L (-6.0 ± 2 pA/pF, n=9) compared to GFP control (-14 ± 2 pA/pF, n=8). Expression of WT LMNA did not affect the ICa,L (-14.2 ± 2.5 pA/pF, n=8) compared to control. Conclusion: We conclude that Lmna N195K mutation results in reduced expression of ion channels and scaffolding proteins in the left ventricle with a significant reduction in peak ICa,L in ventricular myocytes and these may contribute to the mechanism of arrhythmia and dilated cardiomyopathy. 6 samples

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Targeted next-generation sequencing detects novel gene-phenotype associations and expands the mutational spectrum in cardiomyopathie

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