Baralle, D.; (2005) Molecular pathology of neurofibromatosis type 1 (NF1). Doctoral thesis , University of London.

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Abstract

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder caused by mutations in the NF1 gene. Mutation detection in NF1 has been a major challenge due to the large size of the gene and lack of mutational hotspots. This study reports mutation screening of 91 subjects fulfilling NIH NF1 diagnostic criteria in which a mutation detection rate of 89% was achieved using automated comparative sequence analysis (ACSA) and many novel mutations are reported. This detection rate makes this single technique appropriate for routine clinical practice. The data confirms that mutations are evenly distributed along the coding sequence of the NF1 gene and the presence of a second putative functional domain upstream of the GRD at exons 11-17. A related disorder is also studied: Neurofibromatosis-Noonan syndrome and found to be a subtype of NF1 with mutations in the NF1 gene. Abnormalities of pre-mRNA splicing represent an important mechanism by which gene mutations cause disease. Effects on splicing can be predicted from genomic DNA sequence analysis if mutations alter highly conserved canonical splicing signals. However, it is extremely difficult to predict the effects of changes in intronic and exonic sequences not obviously involved in the splicing process. The significance of point mutations, including missense and silent changes are difficult to clarify. This study presents an efficient and simple test using genomic DNA to construct a minigene and analyse the effect on splicing of sequence variations in NFL In particular two mutations are described: an intronic mutation that perturbs NF1 gene splicing and can be rescued by coexpression of an altered U1 snRNA that restores normal base pairing, and a nonsense mutation that interrupts an exonic splice enhancer.

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