Loss of CENP-F Results in Dilated Cardiomyopathy with Severe Disruption of Cardiac Myocyte Architecture

Abstract

Centromere-binding protein F (CENP-F) is a very large and complex protein with many and varied binding partners including components of the microtubule network. Numerous CENP-F functions impacting diverse cellular behaviors have been identified. Importantly, emerging data have shown that CENP-F loss- or gain-of-function has critical effects on human development and disease. Still, it must be noted that data at the single cardiac myocyte level examining the impact of CENP-F loss-of-function on fundamental cellular behavior is missing. To address this gap in our knowledge, we analyzed basic cell structure and function in cardiac myocytes devoid of CENP-F. We found many diverse structural abnormalities including disruption of the microtubule network impacting critical characteristics of the cardiac myocyte. This is the first report linking microtubule network malfunction to cardiomyopathy. Importantly, we also present data demonstrating a direct link between a CENP-F single nucleotide polymorphism (snp) and human cardiac disease. In a proximate sense, these data examining CENP-F function explain the cellular basis underlying heart disease in this genetic model and, in a larger sense, they will hopefully provide a platform upon which the field can explore diverse cellular outcomes in wide-ranging areas of research on this critical protein.

Hypertrophic cardiomyopathy ß-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super-relaxed state

“…The P710R mutation caused significant perturbation in alignment of myofibrils in the mutant cells, a well described phenotype in HCM [51], as well as an increase in the thickness of the z-disc ( Figure 5 ). Increased z-disc thickness has been described in many cardiomyopathies [52–54], and we confirmed this phenotype in human myectomy samples from patients with HCM (data not shown), which suggests that z-disc thickening is a conserved phenotype associated with hypercontractility and hypertrophic remodeling. Finally, we observed cellular hypertrophy which was mediated in part by Akt and ERK.…”

Renal involvement and Strømme syndrome

“…CENPF encodes a protein involved in centromere–kinetochore complex formation, which plays crucial roles in chromosome segregation during mitosis, spindle orientation and primary cilia formation. CENPF knockdown in animal models results in ciliopathy phenotypes, as demonstrated in zebrafish [ 3 ], and CENPF cardiac myocyte-specific deletions lead to adult‐onset dilated cardiomyopathy in mice [ 4 ]. The recently described knockout murine model has revealed several structural kidney abnormalities including the loss of ciliary structures, tubule dilation and disruption of glomeruli, which suggest a specific role for CENPF protein in renal development [ 5 ].…”

Loss of CENPF leads to developmental failure in mouse embryos

“…CENPF plays a key role in mitosis [33] in various cell types such as myocytes [34], breast cancer cells [25], human salivary gland tumor cells [35], and bovine embryos [29]. This is the first study reporting CENPF necessity during embryo preimplantation in mice.…”