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Contribution of elastin to cardiovascular development in zebrafish

Zorrilla, Michelle (2018) Contribution of elastin to cardiovascular development in zebrafish. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Elastin is the main structural protein of elastic fibers that allows tissues in vertebrates to extend and recoil. Heterozygous loss of function mutations in the elastin gene (ELN) can cause supravalvular aortic stenosis (SVAS), a rare obstructive cardiovascular disease typically characterized by a narrowing of the ascending aorta. The association of SVAS with hypertension, valvular defects and other congenital heart defects (CHDs) is of broader public health significance. The main goal of this research is to generate and characterize a set of SVAS-like mutant zebrafish lines. Zebrafish have two elastin genes, elna and elnb. First, I investigated the genetic and transcript diversity of zebrafish elastins by sequencing 46 and 44 overlapping cDNA clones from elna and elnb, respectively. I uncovered substantial variation in from both genes with a total of 79 single nucleotide variants (SNVs) in elna and 89 in elnb. In addition, there were numerous in-del variants and alternative splicing events. To assess the role of elna in zebrafish development, a line of elna homozygous mutants was established. The mutation (elnasa12235 c.264T>A, p.Tyr88*) induces nonsense-mediated decay in a developmentally regulated fashion with close to complete elimination of the mutant transcript starting at 3 days post-fertilization. Phenotypic examination of mutant embryos displayed reduced blood flow, regurgitation, valve and heart looping abnormalities. Regurgitation and valve irregularities was also observed in a mutant adult male. Histological examination of the hearts in adult elna mutant fish showed thinning and loss of the elastic cartilage-like morphology in bulboventricular valves. Further work with larger numbers of fish needs to be done, to obtain reliable estimates of the frequency and possible sex specificity, and clutch-to-clutch variability of valve and other cardiovascular defects in elna mutants. In conclusion, my studies show extensive sequence variation in elna and elnb. Mutants of elna have displayed promise to help explain cardiovascular development and detrimental effects of elastin mutations in humans with SVAS especially with respect to cardiac valve abnormalities.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zorrilla, Michellemiz30@pitt.edumiz300000-0002-7489-9368
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairUrban,
Committee MemberRoman,
Committee MemberTsang,
Committee MemberPhillippi,
Date: 17 September 2018
Date Type: Publication
Defense Date: 1 June 2018
Approval Date: 17 September 2018
Submission Date: 4 June 2018
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 135
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: elastin, eln, supravalvular aortic stenosis, SVAS, zebrafish, cardiovascular development
Date Deposited: 17 Sep 2018 21:03
Last Modified: 01 Jul 2020 05:15


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