Congenital insensitivity to pain (CIP) is an extremely rare inherited disorder characterised by the inability to perceive physical pain from birth, resulting in a number of injuries including self-mutilation, repeated burns and fractures. A number of different genes underlying CIP have been identified over the years and all act principally either to direct development or function of nociceptors. In this dissertation, a number of unrelated families with CIP were recruited and novel missense and splicing mutations in NTRK1, NGF and SCN9A were identified in the cohort. The findings presented in this dissertation demonstrate how mutations in the NTRK1 gene can cause the phenotype of CIP, and increase our knowledge of the functions and the role of key residues of TRKA within the cell. I have verified the importance of NGF in the development of nociceptors and demonstrate the overlapping roles of the precursor proNGF with mature NGF as well as providing insight into the role of proNGF as a neurotrophic molecule, in contrast to the wider consensus. Moreover, I provide further evidence that splicing mutations are also responsible for CIP and highlight that splicing mutations are potentially missed in diagnostic labs. Lastly, I have demonstrated that stem cells can be used to study and generate different types of sensory neurons, indicating a potential use as a suitable platform for investigating monogenic disorders. The identification of novel genes, in addition to the dissection of the residues and pathways of known genes, is essential for the development of new analgesics.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:753435 |
| Date | January 2018 |
| Creators | Shaikh, Samiha Salwa |
| Contributors | Woods, Geoffrey Christopher |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.repository.cam.ac.uk/handle/1810/279060 |
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