Mary E. Sweet

FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy

Summary A genetic etiology has been identified in 30% to 40% of dilated cardiomyopathy (DCM) patients, yet only 50% of these cases are associated with a known causative gene variant. Thus, in order to understand the pathophysiology of DCM, it is necessary to identify and characterize additional genes. In this study, whole exome sequencing in combination with segregation analysis was used to identify mutations in a novel gene, filamin C (FLNC), resulting in a cardiac-restricted DCM pathology. Here we provide functional data via zebrafish studies and protein analysis to support a model implicating FLNC haploinsufficiency as a mechanism of DCM.

Danon disease – dysregulation of autophagy in a multisystem disorder with cardiomyopathy

ABSTRACT Danon disease is a rare, severe X-linked form of cardiomyopathy caused by deficiency of lysosome-associated membrane protein 2 (LAMP-2). Other clinical manifestations include skeletal myopathy, cognitive defects and visual problems. Although individuals with Danon disease have been clinically described since the early 1980s, the underlying molecular mechanisms involved in pathological progression remain poorly understood. LAMP-2 is known to be involved in autophagy, and a characteristic accumulation of autophagic vacuoles in the affected tissues further supports the idea that autophagy is disrupted in this disease. The LAMP2 gene is alternatively spliced to form three splice isoforms, which are thought to play different autophagy-related cellular roles. This Commentary explores findings from genetic, histological, functional and tissue expression studies that suggest that the specific loss of the LAMP-2B isoform, which is likely to be involved in macroautophagy, plays a crucial role in causing the Danon phenotype. We also compare findings from mouse and cellular models, which have allowed for further molecular characterization but have also shown phenotypic differences that warrant attention. Overall, there is a need to better functionally characterize the LAMP-2B isoform in order to rationally explore more effective therapeutic options for individuals with Danon disease. Summary: Danon disease is a severe form of cardiomyopathy, and the molecular mechanisms involved in progression of the disease are poorly understood; however, perturbation of autophagy is likely to play a crucial role.

Obscurin Variants in Patients With Left Ventricular Noncompaction

Left ventricular noncompaction (LVNC) is a rare type of cardiomyopathy, occurring less frequently than hypertrophic cardiomyopathy (HCM) and dilated CM (DCM). In our patient population, we identified a possible association between LVNC and variants in the obscurin ( OBSCN ) gene. Obscurins are giant

Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell–Cell Adhesion Structures

OBJECTIVES The purpose of this study was to assess the phenotype of Filamin C (FLNC) truncating variants in dilated cardiomyopathy (DCM) and understand the mechanism leading to an arrhythmogenic phenotype. BACKGROUND Mutations in FLNC are known to lead to skeletal myopathies, which may have an associated cardiac component. Recently, the clinical spectrum of FLNC mutations has been recognized to include a cardiac-restricted presentation in the absence of skeletal muscle involvement. METHODS A population of 319 U.S. and European DCM cardiomyopathy families was evaluated using whole-exome and targeted next-generation sequencing. FLNC truncation probands were identified and evaluated by clinical examination, histology, transmission electron microscopy, and immunohistochemistry. RESULTS A total of 13 individuals in 7 families (2.2%) were found to harbor 6 different FLNC truncation variants (2 stopgain, 1 frameshift, and 3 splicing). Of the 13 FLNC truncation carriers, 11 (85%) had either ventricular arrhythmias or sudden cardiac death, and 5 (38%) presented with evidence of right ventricular dilation. Pathology analysis of 2 explanted hearts from affected FLNC truncation carriers showed interstitial fibrosis in the right ventricle and epicardial fibrofatty infiltration in the left ventricle. Ultrastructural findings included occasional disarray of Z-discs within the sarcomere. Immunohistochemistry showed normal plakoglobin signal at cell–cell junctions, but decreased signals for desmoplakin and synapse-associated protein 97 in the myocardium and buccal mucosa. CONCLUSIONS We found FLNC truncating variants, present in 2.2% of DCM families, to be associated with a cardiac-restricted arrhythmogenic DCM phenotype characterized by a high risk of life-threatening ventricular arrhythmias and a pathological cellular phenotype partially overlapping with arrhythmogenic right ventricular cardiomyopathy.

Pediatric Cardiomyopathy: New Insight Into Potential Disease Mechanisms.

Cardiomyopathies are clinically heterogeneous disorders that impair heart function. Although cardiomyopathies can occur at any age, pediatric cardiomyopathies in particular have an annual incidence of 1.13 cases in 100,000 children younger than 18 years of age and 8.34 cases per 100,000 infants [(1

Diagnosis, prevalence, and screening of familial dilated cardiomyopathy

Introduction: Dilated cardiomyopathy (DCM) is the most common cardiomyopathy and occurs often in families. As an inherited disease, understanding the significance of diagnostic procedures and genetic screening within families is of utmost importance. Areas covered: Genetic studies have shown that in 30 – 40% of familial DCM (FDC) cases a causative genetic mutation can be identified. Successful genetic analysis is highly dependent on close examination of patient and family history, and clinical guidelines exist recommending genetic testing to aid in the evaluation of family members at risk of developing FDC. Clinical genetic testing offers a resource for families to identify the etiology of their disease and in some cases may provide clinical prognostic insight. Expert opinion: As an inherited disease, future FCD studies will focus on elucidating the remaining 60 – 70% of genetic causes in inherited cases and the pathogenic mechanisms leading to the phenotype. Specifically, a focus on regulatory regions, copy number variation, genetic and environmental modifiers and functional confirmatory investigations will be essential.

Genetic Infiltrative Cardiomyopathies

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.

nihexporter: an R package for NIH funding data

1.1 Motivation The National Institutes of Health (NIH) is the major source of federal funding for biomedical research in the United States. Analysis of past and current NIH funding can illustrate funding trends and identify productive research topics, but these analyses are conducted ad hoc by the institutes themselves and only provide a small glimpse of the available data. The NIH provides free access to funding data via NIH EXPORTER, but no tools have been developed to enable analysis of this data. 1.2 Results We developed the nihexporter R package, which provides access to NIH EXPORTER data. We used the package to develop several analysis vignettes that show funding trends across NIH institutes over 15 years and highlight differences in how institutes change their funding profiles. Investigators and institutions can use the package to perform self-studies of their own NIH funding. 1.3 Availability The nihexporter R package can be installed via github. 1.4 Implementation The nihexporter package is implemented in the R Statistical Computing Environment. 1.5 Contact Jay Hesselberth jay.hesselberth@gmail.com, University of Colorado School of Medicine