Fibulin-4 is an extracellular matrix protein which plays an essential function in the assembly of elastic fibres, and may be involved in the modulation of TGFβ bioavailability and smooth muscle cell differentiation. Mutations in fibulin-4 can cause autosomal recessive cutis laxa, a frequently lethal connective tissue disorder. Although patient studies have provided some insights into the pathological mechanisms of this disease, a detailed analysis of the consequences of fibulin-4 mutations on a molecular and cellular level was required.The findings presented in this thesis demonstrate that cutis laxa-causing fibulin-4 mutations may lead to reduced extracellular levels of fibulin-4 due to its increased susceptibility to protease degradation and misfolding/aggregation. An accumulation of autophagic vesicles was observed, indicating a blockage of autophagy, possibly due to intracellular accumulation of aggregated/misfolded mutant protein. In the extracellular matrix, mutations affected the ability of fibulin-4 to interact with the major components of the elastic fibre assembly, heparin, LTBP-1 and fibronectin. In addition, fibulin-4 mutations generally reduced expression levels of elastic fibre assembly components. In summary, these findings contribute to the understanding of fibulin-4 associated cutis laxa, and provide a basis upon which future therapeutic interventions may be developed.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:576854 |
| Date | January 2013 |
| Creators | Simpson, Andreja |
| Contributors | Kielty, Catherine; Baldock, Clair |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/fibulin4-mutations-in-cutis-laxa(fcf5936a-e6a4-42a0-b58a-a16876b0f01f).html |
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