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Multigenic etiology of hypoplastic left heart syndrome insights from a novel mouse model

Saeed, Shazina (2014) Multigenic etiology of hypoplastic left heart syndrome insights from a novel mouse model. Master's Thesis, University of Pittsburgh. (Unpublished)

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Hypoplastic left heart syndrome (HLHS) is a complex congenital heart defect characterized by severe hypoplasia of the left ventricle (LV) along with stenosis/atresia of the aortic and mitral valves. HLHS patients show an incidence of 4-9 in 100,000 live births. Clinical studies have indicated that HLHS is a complex disease that is heritable, but no specific gene(s) have been identified. Despite the recent surgical advancements in the treatment of HLHS, understanding the developmental and genetic mechanisms associated with HLHS have proved to be a challenge due to the lack of an animal model.
In our study, we recovered 7 mutant mouse lines with HLHS from a large-scale recessive genetic screen with ENU mutagenesis. Further analysis of one HLHS mutant line, Ohia, showed that the HLHS phenotype is indeed heritable. Whole exome sequencing of two Ohia HLHS mutants revealed both were homozygous for mutations in five genes: Prolidase, NAD synthetase, Protocadherin a9, Sin3A-associated polypeptide 130 and N-acetyltransferase-ESCO1. GO term and KEGG ontology analysis of RNAseq data from heart tissue of E13.5,E14.5 and E18.5 Ohia mutants and littermate controls showed down-regulation of many genes involved in mitochondrial dynsfunction, such as oxidative phosphorylation, Parkinson’s, and Alzheimer’s disease . Genes involved in pathways of cancer, extracellular matrix-receptor interaction, focal adhesion, TGF-beta signaling, and Wnt signaling showed up regulation. These pathway enrichments are similar to results previously shown with microarray transcript profiling of human HLHS heart tissue.
In conclusion, we have generated the first mouse model for HLHS and showed it closely mirror not only the structural heart defect but also the metabolic changes seen in human HLHS patients. Using this mouse HLHS model, we will be able to interrogate the developmental pathways and molecular etiology underlying HLHS. Dissecting these elements would prove to be of immense public health significance, as despite the medical advances, every year 4-9 children in 100,000 live births are born with HLHS, and very few make it to adulthood. HLHS is universally fatal with 90% of deaths occurring in the first month of life in the absence of surigical treatment.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Saeed, Shazinashs109@pitt.eduSHS109
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorLo, Cecilia Wcel36@pitt.eduCEL36
Committee MemberFerrell, Robert E.rferrell@helix.hgen.pitt.eduRFERRELL
Committee MemberIlyas, Kambohkamboh@pitt.eduKAMBOH
Date: 27 June 2014
Date Type: Publication
Defense Date: 27 January 2014
Approval Date: 27 June 2014
Submission Date: 12 April 2014
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 57
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Public Health Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Congenital heart diseases, Hypoplastic left heart syndrome.
Date Deposited: 27 Jun 2014 22:02
Last Modified: 01 May 2019 05:15


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