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Fraser syndrome and mouse blebbed mutants.

Jadeja, S.; (2006) Fraser syndrome and mouse blebbed mutants. Doctoral thesis , University of London. Green open access

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Fraser syndrome is a multisystem malformation, the main features being cryptophthalmos, syndactyly and renal defects. Mouse blebbed mutants provide a model for Fraser syndrome, with mutations in five blebbed loci giving similar phenotypes to Fraser syndrome. The condition is genetically heterogeneous and the first disease locus to be identified, FRAS1, encodes a protein with similarity to the sea urchin extracellular matrix blastocoelar protein ECM3. The domain structure of FRAS1 suggests a structural role within the extracellular matrix as well as in cell signalling. Mutations in FRAS1, and Frasl in the blebbed (bl) mouse, have been identified that result in the premature termination of the protein. Mutations in the Freml gene have been shown to underly the head blebs (heb) phenotype. In this thesis, a missense mutation at a second human locus is described, the affected gene FREM2, having homology to a gene closely linked to the murine myelencephalic blebs (my) locus. A genetrap within Freml is shown to have a similar phenotype to the other blebs mutants. The expression pattern of Freml is studied and auditory defects in the my mice are identified and analysed. Some functional analyses of Frasl was carried out suggesting a role for Frasl in binding BMPs. It is also shown that the loss of the cytoplasmic multi-PDZ domain protein glutamate receptor interacting protein 1 (GRIP1) results in a phenotype similar to that of Fraser syndrome. In the eye blebs (eb) mouse a deletion has been detected covering two coding exons that disrupts the (Gripl) gene, resulting in a premature termination. These mouse models for Fraser syndrome should provide important insights into the development of epithelial structures, as well as eye and kidney development and enable us to study the role of Fras-Frem proteins in other organs such as the heart and ear.

Type: Thesis (Doctoral)
Title: Fraser syndrome and mouse blebbed mutants.
Identifier: PQ ETD:592064
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by Proquest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
URI: https://discovery.ucl.ac.uk/id/eprint/1444755
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