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Title: Identification and characterisation of cardiac defects in mouse models isolated from a random chemical mutagenesis screen
Author: Stephen, Louise
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2013
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Congenital heart defects represent a major burden on medical resources, being the leading cause of infant death in the developed world. An average of 1% of all live births are thought to involve a congenital heart defect. The mouse has long been a key model in the study of mammalian cardiac development, with traditional mouse knockouts leading the way. As next generation sequencing technologies progress, random mutagenesis screens offer a phenotype driven approach to the identification of new genes involved in developmental pathways. A targeted ENU mutagenesis screen for mouse chromosome 11 lead to the isolation of the L11Jus27 line, from which two embryonic lethal mutations were isolated. A combination of meiotic mapping and high throughput sequencing has identified a candidate mutation in the K27 mouse, in the pre-mRNA spliceosome gene, Prpf8, implicated in retinitis pigmentosa. Morphological analysis and ultrasound have identified a midgestation-lethal phenotype, with K27 mice exhibiting a distended heart tube and reversal of cardiac looping. Expression analysis suggests the K27 mouse may represent a Pitx2 independent model of laterality defects. The Embryonic Hydrocephalus and Cardiac defects (EHC) mutation has previously been identified in the nonmuscle myosin gene, Myh10. A combination of histological analysis and protein localisation studies, have been used to identify a specific requirement for Myh10 in the development of the epicardium. Loss of epicardial adhesion leads to a loss of coronary vasculature. Together the L11Jus27mouse lines demonstrate a role for mutagenesis screens in the study of clinically applicable mammalian models.
Supervisor: Hentges, Kathryn Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available