BAG3 myofibrillar myopathy presenting with cardiomyopathy

Konersman, Chamindra G.; Bordini, Brett J.; Scharer, Gunter; Lawlor, Michael W.; Zangwill, Steven; Southern, James F.; Amos, Louella B.; Geddes, Gabrielle C.; Kliegman, Robert M.; Collins, Michael

doi:10.1016/j.nmd.2015.01.009

Cited by 65 publications

(61 citation statements)

References 25 publications

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“…Patients harboring this single allelic substitution displayed a fulminant muscular dystrophy with rapidly progressive limb and axial muscle weakness in early childhood, in the second decade of life accompanied by respiratory insufficiency and the development of cardiomyopathy, often resulting in early death. This phenotype of human BAG3-related MFM was verified by other studies; additionally, an axonal neuropathy with giant axons was observed in some cases (Odgerel et al, 2010; Jaffer et al, 2012; Lee et al, 2012; Konersman et al, 2015; Kostera-Pruszczyk et al, 2015). Notably, the heterozygous Pro209Leu BAG3 mutation, which is situated in the second of the two conserved IPV motifs of BAG3, seems to be a spontaneous mutation that occurs de novo in the early embryonic development (Odgerel et al, 2010).…”

Section: The Multifunctional Hsp70 Co-chaperone Bag3supporting

confidence: 84%

The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease

Stürner

Behl

2017

Front. Mol. Neurosci.

161

167

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In neurons, but also in all other cells the complex proteostasis network is monitored and tightly regulated by the cellular protein quality control (PQC) system. Beyond folding of newly synthesized polypeptides and their refolding upon misfolding the PQC also manages the disposal of aberrant proteins either by the ubiquitin-proteasome machinery or by the autophagic-lysosomal system. Aggregated proteins are primarily degraded by a process termed selective macroautophagy (or aggrephagy). One such recently discovered selective macroautophagy pathway is mediated by the multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3). Under acute stress and during cellular aging, BAG3 in concert with the molecular chaperones HSP70 and HSPB8 as well as the ubiquitin receptor p62/SQSTM1 specifically targets aggregation-prone proteins to autophagic degradation. Thereby, BAG3-mediated selective macroautophagy represents a pivotal adaptive safeguarding and emergency system of the PQC which is activated under pathophysiological conditions to ensure cellular proteostasis. Interestingly, BAG3-mediated selective macroautophagy is also involved in the clearance of aggregated proteins associated with age-related neurodegenerative disorders, like Alzheimer’s disease (tau-protein), Huntington’s disease (mutated huntingtin/polyQ proteins), and amyotrophic lateral sclerosis (mutated SOD1). In addition, based on its initial description BAG3 is an anti-apoptotic protein that plays a decisive role in other widespread diseases, including cancer and myopathies. Therefore, in the search for novel therapeutic intervention avenues in neurodegeneration, myopathies and cancer BAG3 is a promising candidate.

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Section: The Multifunctional Hsp70 Co-chaperone Bag3supporting

confidence: 84%

The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease

Stürner

Behl

2017

Front. Mol. Neurosci.

161

167

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“…Aggregation of filamin‐C in cell culture and muscle tissue has been demonstrated previously for a nonsense mutation (p.W2710X) causing MFM as well as for some HCM mutations [Vorgerd et al., ; Valdés‐Mas et al., ]; this cytoplasmic aggregation is presumably what causes the observed deleterious effects. Likewise, cardiac protein aggregates have also been described to result from mutations in other genes such as CRYAB [Vicart et al., ], DES [Muñoz‐Mármol et al., ], BAG3 [Konersman et al., ], and PLN [Karakikes et al., ]. Therefore, we investigated whether our mutants (p.S1624L and p.I2160F) cause such an accumulation in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Mutations inFLNCare Associated with Familial Restrictive Cardiomyopathy

et al. 2016

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Individuals affected by restrictive cardiomyopathy (RCM) often develop heart failure at young ages resulting in early heart transplantation. Familial forms are mainly caused by mutations in sarcomere proteins and demonstrate a common genetic etiology with other inherited cardiomyopathies. Using next-generation sequencing, we identified two novel missense variants (p.S1624L; p.I2160F) in filamin-C (FLNC), an actin-cross-linking protein mainly expressed in heart and skeletal muscle, segregating in two families with autosomal-dominant RCM. Affected individuals presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases. Histopathology of heart tissue from patients of both families showed cytoplasmic inclusions suggesting protein aggregates, which were filamin-C specific for the p.S1624L by immunohistochemistry. Cytoplasmic aggregates were also observed in transfected myoblast cell lines expressing this mutant filamin-C indicating further evidence for its pathogenicity. Thus, FLNC is a disease gene for autosomal-dominant RCM and broadens the phenotype spectrum of filaminopathies.

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“…Associated features include sinus node dysfunction, atrioventricular block, supraventricular and ventricular tachycardias, HF, and sudden death. 46,[48][49][50][51][52][53] Barth Syndrome BTHS is a rare X-linked, recessive mitochondrial myopathy that was initially described in 1983 among a Dutch pedigree of male infants with dilated cardiomyopathy, neutropenia, and skeletal myopathy. 54 As of 2013, 151 cases had been described worldwide with an estimated incidence between 1 in 140 000 and 1 in 670 000 births.…”

Section: Myofibrillar Myopathymentioning

confidence: 99%

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

Feingold¹,

Mahle²,

Auerbach³

et al. 2017

Circulation

211

195

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For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes. N euromuscular diseases (NMDs) encompass a broad spectrum of diagnoses with overlapping but distinct phenotypes. Common to many NMDs is cardiac involvement. Although the past 3 decades have seen marked advances in our understanding of many NMDs, significant gaps in knowledge remain on how best to approach cardiac care in these patients. For example, survival in Duchenne muscular dystrophy (DMD) has been extended through the use of glucocorticoid use and respiratory support, yet cardiac complications remain a significant cause of morbidity and mortality.1-3 To achieve further gains in care, we will need to improve our understanding of the pathophysiologies driving cardiac involvement in NMDs and advance treatments aimed at preventing the progression of heart failure (HF) and sudden death in NMDs. The recently published findings of an expert working group on cardiac involvement in DMD, which outlined key gaps in knowledge and made specific recommendations aimed at improving diagnosis and management, are a step toward this goal. 4 In this statement, we include a comprehensive overview of the major categories of NMDs with cardiac involvement. For each, a brief background of the gene defect(s), common clinical manifestations (particularly cardiac findings), and current therapies is summarized. Gaps in knowledge are highlighted, and where possible, clinical treatment suggestions are made by the expert writing group appointed by the American Heart Association to review the available literature. Selection of the writing group was performed in accordance with the American Heart Association's conflict-of-interest management policy. Participants volunteered to write sections relevant to their expertise and experience. CLINICAL STATEMENTS AND GUIDELINESconducted a general search of the literature, restricted to human subjects research published between 1980 and 2016. Drafts of each section were written and sent to the chair of the writing group for incorporation into a single document, which was then edited. The edited document was discussed electron...

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BAG3 myofibrillar myopathy presenting with cardiomyopathy

Cited by 65 publications

References 25 publications

The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease

The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease

Mutations inFLNCare Associated with Familial Restrictive Cardiomyopathy

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

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