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Title: Human TBX22 expression and protein-DNA interactions
Authors: Lisgo, Steven Newton
Issue Date: 2010
Publisher: Newcastle University
Abstract: Cleft palate is one of the most common birth abnormalities. Figures published in 2006 by the American Centres for Disease Control and Prevention, report the incidence of those born in the United States with a cleft palate without the presence of a cleft lip (CPI) to be 6.39 for every 10000 in the three years between 1999 to 2001 and for cleft lip in association with a cleft palate (CLP) to be even greater - 10.48 per 10000 live births. In 2001, Braybrook and colleagues reported that mutations in the TBX22 gene cause X-linked cleft palate (CPX), a disease characterised by a cleft of the secondary palate and is often seen in association with ankyloglossia (tongue-tie) (Braybrook et al. 2001). A cleft of the secondary palate arises as a consequence of disturbance to correct development during palatogenesis: an anomaly in palatal shelf growth; delayed or failed shelf elevation; defective shelf fusion or a failure of medial edge epithelium cell death. This thesis reveals that the expression of TBX22 during these key developmental events in human embryos is consistent with the phenotype seen in CPX. To enable an investigation for TBX22 target genes, a DNA binding sequence is determined for the TBX22 protein. This sequence is used to generate a generic TBX22 DNA binding site, the presence of which is screened for in promoter regions, defined as 2kb upstream of transcription start sites. 132 genes were selected as candidate TBX22 targets on the basis that they underlie human disorders that include a cleft palate. The screen shows that 28 of these genes have at least one perfect or near perfect match to the generic TBX22 DNA binding site. Of these, only two both contained a perfect TBX22 generic DNA binding site and mouse mutants also had cleft palates: SUMO1 and MSX1. Interaction between SUMO1 and TBX22 has already been shown (Andreou et al. 2007). This study investigated MSX1 as a downstream target of TBX22 using a luciferase reporter gene construct in vitro. The results showed that in the presence of TBX22, the luciferase signal was reduced and support MSX1 being a downstream target gene of TBX22. These findings further the understanding of the molecular networks regulating craniofacial development. Unravelling these complex interactions is crucial to identifying the mechanisms of oro-facial clefting, important steps towards improved methods of counselling, treatment and prevention of these common birth disorders.
Description: PhD Thesis
Appears in Collections:Institute of Human Genetics

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