We examined the prevalence, genotype-phenotype correlation, and natural history of lamin A/C gene (LMNA) mutations in subjects with dilated cardiomyopathy (DCM).
Mutations in LMNAhave been found in ...patients with DCM with familial conduction defects and muscular dystrophy, but the clinical spectrum, prognosis, and clinical relevance of laminopathiesin DCM are unknown.
A cohort of 49 nuclear families, 40 with familial DCM and 9 with sporadic DCM (269 subjects, 105 affected), was screened for mutations in LMNAusing denaturing high-performance liquid chromatography and sequence analysis. Bivariate analysis of clinical predictors of LMNAmutation carrier status and Kaplan-Meier survival analysis were performed.
Mutations in LMNAwere detected in four families (8%), three with familial (R89L, 959delT, R377H) and one with sporadic DCM (S573L). There was significant phenotypic variability, but the presence of skeletal muscle involvement (p < 0.001), supraventricular arrhythmia (p = 0.003), conduction defects (p = 0.01), and “mildly” DCM (p = 0.006) were predictors of LMNAmutations. The LMNAmutation carriers had a significantly poorer cumulative survival compared with non-carrier DCM patients: event-free survival at the age of 45 years was 31% versus 75% in non-carriers.
Mutations in LMNAcause a severe and progressive DCM in a relevant proportion of patients. Mutation screening should be considered in patients with DCM, in particular when clinical predictors of LMNAmutation are present, regardless of family history.
Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin (DES) gene. Mutations in the central 2B domain of DES cause skeletal muscle ...disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in dilated cardiomyopathy (DCM) without skeletal muscle disease is not known.
Denaturing high-performance liquid chromatography was used to screen DES for mutations in 116 DCM families from the Familial Dilated Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13 and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects on cytoskeletal desmin network architecture were analyzed with confocal microscopy. Five novel missense DES mutations, including the first localized to the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection of DES mutations in the 2B domain severely disrupted the fine intracytoplasmic staining of desmin, causing clumping of the desmin protein. A tail domain mutation (Val459Ile) showed milder effects on desmin cytoplasmic network formation and appears to be a low-penetrant mutation restricted to black subjects.
The prevalence of DES mutations in DCM is between 1% and 2%, and mutations in the 1A helical domain, as well as the 2B rod domain, are capable of causing a DCM phenotype. The lack of severe disruption of cytoskeletal desmin network formation seen with mutations in the 1A and tail domains suggests that dysfunction of seemingly intact desmin networks is sufficient to cause DCM.
Dilated cardiomyopathy (DCM) commonly causes heart failure and shows extensive genetic heterogeneity that may be amenable to newly developed next-generation DNA sequencing of the exome. In this study ...we report the successful use of exome sequencing to identify a pathogenic variant in the TNNT2 gene using segregation analysis in a large DCM family. Exome sequencing was performed on three distant relatives from a large family with a clear DCM phenotype. Missense, nonsense, and splice variants were analyzed for segregation among the three affected family members and confirmed in other relatives by direct sequencing. A c.517T C>T, Arg173Trp TNNT2 variant segregated with all affected family members and was also detected in one additional DCM family in our registry. The inclusion of segregation analysis using distant family members markedly improved the bioinformatics filtering process by removing from consideration variants that were not shared by all affected subjects. Haplotype analysis confirmed that the variant found in both DCM families was located on two distinct haplotypes, supporting the notion of independent mutational events in each family. In conclusion, an exome sequencing strategy that includes segregation analysis using distant affected relatives within a family represents a viable diagnostic strategy in a genetically heterogeneous disease like DCM.
Pediatric Cardiomyopathy Mestroni, Luisa, MD; Sweet, Mary E., BA; Taylor, Matthew R.G., MD, PhD
Journal of the American College of Cardiology,
02/2016, Letnik:
67, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Using a combination of homozygosity mapping, whole exome sequencing, and candidate gene screening, the group identified homozygous premature stop codon mutations in ALPK3 and, from immunohistological ...observations of heart tissue, suggest potential mechanisms for further exploration. Expression studies in mouse embryos and adult tissues have shown that Alpk3, also known as Midori, is expressed in the fetal heart as well as the adult heart and skeletal muscle, and it localizes to the nucleus where it may regulate transcription (5). Because Alpk3-deficient mice exhibit indistinct intercalated discs, Alpk3 may be necessary for their proper formation (4).
Danon disease is a severe X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2 (LAMP-2). Clinical manifestations are phenotypically diverse and consist of hypertrophic ...and dilated cardiomyopathies, skeletal myopathy, retinopathy, and intellectual dysfunction. Here, we investigated the metabolic landscape of Danon disease by applying a multi-omics approach and combined structural and functional readouts provided by Raman and atomic force microscopy. Using these tools, Danon patient-derived cardiac tissue, primary fibroblasts, and human induced pluripotent stem cells differentiated into cardiomyocytes (hiPSC-CMs) were analyzed. Metabolic profiling indicated LAMP-2 deficiency promoted a switch toward glycolysis accompanied by rerouting of tryptophan metabolism. Cardiomyocytes' energetic balance and NAD+/NADH ratio appeared to be maintained despite mitochondrial aging. In turn, metabolic adaption was accompanied by a senescence-associated signature. Similarly, Danon fibroblasts appeared more stress prone and less biomechanically compliant. Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.
Genetic Infiltrative Cardiomyopathies Sweet, Mary E; Mestroni, Luisa; Taylor, Matthew R G
Heart failure clinics,
04/2018, Letnik:
14, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Infiltrative cardiomyopathies are characterized by abnormal accumulation or deposition of substances in cardiac tissue leading to cardiac dysfunction. These can be inherited, resulting from mutations ...in specific genes, which engender a diverse array of extracardiac features but overlapping cardiac phenotypes. This article provides an overview of each inherited infiltrative cardiomyopathy, describing the causative genes, the pathologic mechanisms involved, the resulting cardiac manifestations, and the therapies currently offered or being developed.
Nuclear factor κB (NF-κB) signaling in cardiac myocytes causes disease in a mouse model of arrhythmogenic cardiomyopathy (ACM) by mobilizing CCR2-expressing macrophages that promote myocardial injury ...and arrhythmias. Buccal mucosa cells exhibit pathologic features similar to those seen in cardiac myocytes in patients with ACM.
We sought to determine if persistent innate immune signaling via NF-κB occurs in cardiac myocytes in patients with ACM and if this is associated with myocardial infiltration of proinflammatory cells expressing CCR2. We also determined if buccal mucosa cells from young subjects with inherited disease alleles exhibit NF-κB signaling.
We analyzed myocardium from ACM patients who died suddenly or required cardiac transplantation. We also analyzed buccal mucosa cells from young subjects with inherited disease alleles. The presence of immunoreactive signal for RelA/p65 in nuclei of cardiac myocytes and buccal cells was used as a reliable indicator of active NF-κB signaling. We also counted myocardial CCR2-expressing cells.
RelA/p65 signal was seen in numerous cardiac myocyte nuclei in 34 of 36 cases of ACM but not in 19 age-matched control individuals. Cells expressing CCR2 were increased in patient hearts in numbers directly correlated with the number of cardiac myocytes showing NF-κB signaling. NF-κB signaling was observed in buccal cells in young subjects with active disease.
Patients with clinically active ACM exhibit persistent innate immune responses in cardiac myocytes and buccal mucosa cells, reflecting a local and systemic inflammatory process. Such individuals may benefit from anti-inflammatory therapy.
PDF
