New insights in the molecular pathogenesis of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1; OMIM 162200) is one of the most common autosomal dominant genetic disorders, affecting approximately 1 in 3500 individuals worldwide. The most common clinical manifestations are pigmentary abnormalities together with the development of benign peripheral nerve sheath tumors or neurofibromas. In addition, NF1 patients are prone to a pleiotropy of other phenotypic features. Determining when and in what cell type the crucial molecular defect actually occurs has proven to be surprisingly difficult for many NF1-related symptoms. Impeding factors include the large size of the NF1 gene, the presence of several NF1 pseudogenes, the complex interactions between cell types within affected tissues, and the NF1 heterozygous state of all cells in the body. The major goal of this thesis was to gain insight into the developmental concepts underlying various NF1-related symptoms by exploiting improved somatic mutation detection strategies on a diverse spectrum of cellular entities