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The human T transcription factor: A study of genetics and function

Papapetrou, Charalambos; (1999) The human T transcription factor: A study of genetics and function. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The human T gene is a member of a family of transcription factors, the T-box genes, which play an important role during embryogenesis. T is expressed early in development in the primitive streak, axial mesoderm, notochord and tail bud and is essential for normal mesoderm development and notochord differentiation. Mouse T mutations are lethal and heterozygotes have features that resemble neural tube defects and sacral agenesis in man. This thesis describes the genetic analysis of the human T gene in healthy individuals and in neural tube defect and sacral agenesis patients. Eight new polymorphisms were identified by a combination of SSCP and sequence analyses and three of these involve an amino acid change in evolutionary conserved domains; Gly177Asp in the DNA binding domain and Gly356Ser and Asn369Ser in a transcriptional activation domain. An association between an allele (TIVS7-2) and a particular haplotype (T363.G530.IVS7-2) and susceptibility to spina bifida was detected. Analysis of T in sacral agenesis patients identified a rare variant Ala338Val in the transcriptional activation domain, in a single patient and his mother. Overall it was concluded that T may play a role in the aetiology of neural tube defects and sacral agenesis, but accounts for only a small proportion of the genetic component of susceptibility to these disorders. The proximal promoter of the human T gene was cloned, sequenced and compared with the mouse sequence in a search for conserved regulatory elements. Several potential motifs were identified, the most significant of which was a 30 bp region conserved not only between man and mouse, but also Xenopus. In vitro DNA/protein binding studies were carried out to demonstrate that human T protein is able to bind to a DNA motif known to be the target for mouse T protein. In addition, it was demonstrated that both human and mouse T bind their DNA target as a dimer and could form a heterodimer. It was shown that the Asp177 variant of the DNA binding domain reduces the stability of T dimer formation. Mouse Tbx6 protein, another member of the T-box family, was shown to bind to the same DNA target, but it was demonstrated that T and Tbx6 are not likely to bind this target as a heterodimer. The human homologue of the TBX6 gene was cloned, sequenced and mapped to chromosome 16p11.2. Expression studies showed that TBX6 is expressed in the notochord and tail bud in the early stages of development, but also in a wide range of adult tissues. A novel member of the T-box gene family, designated T-like, was identified by sequence analysis of PCR products. Preliminary analysis suggests that T-like expression overlaps with that of T during development, but is also characterised by a second phase of expression in adult life.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The human T transcription factor: A study of genetics and function
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences; T box genes
URI: https://discovery.ucl.ac.uk/id/eprint/10101123
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