Repository logo
 

Characterization of zebrafish models of filamin C related cardiomyopathy

Simple item page
dc.contributor.authorAlnefaie, Rasha M., author
dc.contributor.authorGarrity, Deborah, advisor
dc.contributor.authorReddy, A. S. N., committee member
dc.contributor.authorLybourn, Paul, committee member
dc.contributor.authorMuller, Racheal, committee member
dc.date.accessioned2019-06-14T17:06:33Z
dc.date.available2020-06-10T17:06:51Z
dc.date.issued2019
dc.description.abstractCardiomyopathies are a group of cardiac muscle diseases characterized by abnormal function and/or structure of the myocardium which cause arrhythmia, heart failure or sudden death. In many cases, cardiomyopathy is a genetic disease and the majority of inherited cases are caused by mutations in genes that encode cardiac costameric and sarcomeric proteins. Cardiomyopathies include different types, such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and arrythmogenic cardiomyopathy (ARCM). These groups of disorders can have common cellular phenotypes and mechanisms. To date, few studies have described the roles of filamin C in cardiac development or explained how mutations in filamin C cause cardiomyopathic disease. Due to the lack of a suitable animal model, the pathological mechanisms underlying this disease and the role of filamin C in cardiac development remain unclear. Here, we created a zebrafish loss-of-function model for two flnc paralogous genes. We investigated several genetic lines bearing mutations in filamin C that target different sites of the gene. As for humans, zebrafish mutants exhibited variable penetrance and variable expressivity. Double flnca and flncb mutant hearts exhibited more pronounced cardiac morphological defects compared to single mutants, leading to the conclusion that these paralogs play redundant roles in zebrafish heart development. The cardiac morphological phenotype of double flnc mutant embryos is characterized by a decrease in cardiac output and stroke volume as is also observed in patients who suffer from cardiomyopathies. Using a transgenic line expressing GFP in cardiac z-discs, we find that knockdown of flnca and flncb via morpholinos and double flnca and flncb mutant hearts exhibited irregular z-discs. In support of this finding, ultrastructural analysis by transmission electronic microscopy for flncb morphant embryos and double flnca and flncb mutants indicated disorganized myofibrils with fewer consecutive sarcomeres. Particularly, z-discs were irregular or apparently absent, and numerous small vacuoles and potentially autophagous vesicles were observed. Additionally, through double flnca and flncb mutant, we demonstrated that filamin C is required for normal cardiomyocyte morphology and microfilament arrangement. In summary, the zebrafish model demonstrates an essential requirement for filamin C function during heart and skeletal muscle development. Depletion of filamin C impairs both sarcomerogenesis and alters the cytoskeletal architecture of cardiomyocytes.
dc.format.mediumborn digital
dc.format.mediumdoctoral dissertations
dc.identifierAlnefaie_colostate_0053A_15402.pdf
dc.identifier.urihttps://hdl.handle.net/10217/195360
dc.languageEnglish
dc.language.isoeng
dc.publisherColorado State University. Libraries
dc.relation.ispartof2000-2019
dc.rightsCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.
dc.titleCharacterization of zebrafish models of filamin C related cardiomyopathy
dc.typeText
dcterms.embargo.expires2020-06-10
dcterms.embargo.terms2020-06-10
dcterms.rights.dplaThis Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
thesis.degree.disciplineCell and Molecular Biology
thesis.degree.grantorColorado State University
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Alnefaie_colostate_0053A_15402rev.pdf
Size:
4.69 MB
Format:
Adobe Portable Document Format
Description:
Download

Collections

2000-2019
Theses and Dissertations