Von Recklinghausen neurofibromatosis (NF1) and neurofibromatosis type 2 (NF2) are autosomal dominant inherited disorders which predispose carriers to various benign and malignant tumours. Both genes are thought to act as tumour suppressors with inactivation of both alleles resulting in abnormal cell growth. By inference from other hereditary cancer syndromes, it has been hypothesized that somatic mutation at the NF1 and NF2 loci is involved in the development of sporadic tumors of the types found with increased prevalence in these disorders. / In addition to other malignancies, individuals with NF1 are at an increased risk to develop astrocytomas and rhabdomyosarcomas. We have therefore screened 34 astrocytomas for loss of heterozygosity (LOH) using three NF1-derived cDNA probes, and have found no abnormalities. / Half of NF2 patients develop spinal and cranial meningiomas, while fully 90% develop bilateral vestibular schwannomas. In addition, loss of heterozygosity (LDH) of chromosome 22 markers is known to occur in malignant melanona and breast cancer. To evaluate the role of NF2 in sporadic cancer, single-stranded conformation polymorphism analysis (SSCP) was carried out on all 17 exons of the NF2 gene. 57 variants have been found, 44 in meningiomas, 12 in schwannomas, and a single variant in a melanoma. / Most of these represent inactivating mutations (frameshift, splice-site, and nonsense), as determined by direct sequencing. Since the majority of these changes occur in tumours previously shown to have LOH at chromosome 22 markers flanking NF2, our results support a tumour suppressor role for this gene in meningiomas. In addition, given that 40% of our tumours do not show LOH over this region, we propose that at least one other gene is involved in the development of this latter subset of meningiomas. (Abstract shortened by UMI.)

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No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis type I (NF1) is a common genetic disease that affects over 200,000 patients in North America, Europe, and Japan. Individuals with NF1 display a wide variety of pathologies; importantly, 15-40% of NF1 patients are affected by plexiform neurofibromas. Neurofibromas are complex tumors consisting of tumorgenic Schwann cells surrounded by endothelial cells, fibroblasts, and inflammatory mast cells. These peripheral nerve sheath tumors contribute significantly to the morbidity and mortality associated with NF1. Currently, no medical therapies exist for treating neurofibromas. Recent evidence indicates that the hematopoietic tumor microenvironment carries out a crucial function in the formation of plexiform neurofibromas. Neurofibromatosis is the result of mutations at the NF1 locus, which encodes the GTPase activating protein neurofibromin. Neurofibromin is a negative regulator of the proto-oncogene Ras. Ras hyperactivation is the molecular basis of NF1 associated phenotypes, and it has been demonstrated that restoration of Ras signaling to wild type levels can correct NF1 associated phenotypes in vitro and in vivo. In keeping with the long term goal of detecting potential molecular targets for medical therapies to treat human plexiform neurofibromas, we have identified the kinase Pak1 as a possible downstream intermediary of Ras signaling in NF1 deficient cells. Studies described here utilized murine genetic models to study the effects of genetic inactivation of Pak1 on molecular signaling and cellular functions related to neurofibromas. We demonstrate that inactivation of Pak1 leads to correction of SCF mediated gain-in-function phenotypes seen in Nf1 haploinsufficient mast cells, in vivo and in vitro. However, by using a conditional Nf1 knockout mouse that is a reliable model of plexiform neurofibroma formation, we shown that loss of Pak1 alone in the hematopoeitic compartement is not sufficient to prevent neurofibroma formation. Additionally, we describe a key role for Pak1 in regulating PDGF and TGF-β mediated fibroblast functions, in vitro and in vivo. These studies provide insight into the causes of debilitating tumors related to a common genetic disease, and this research could potentially lead to the development of medical therapies for these tumors, increasing the quality of life for tens of thousands of affected individuals each year.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.

In 1993, the Neurofibromatosis type 2 gene product, merlin or schwannomin was identified by positional cloning and was mapped to chromosome 22q 12 (Rouleau et al., 1993; Trofatter et al., 1993). Individuals with mutations in this gene fail to produce normal merlin and develop the neural disorder, Neurofibromatosis type 2. The disease is characterized by growth of bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, balance dysfunction, meningiomas and other tumors of the nervous system (Ruggieri and Huson, 1999). To date, merlin's molecular mechanism of function as a tumor suppressor protein in cells is not known. In this thesis, we examined merlin's interaction with the epidermal growth factor receptor, erbB2, a receptor known to cause Schwann cell growth. Immunoprecipitation and indirect in vitro protein binding assay using total cell lysate from rat Schwann cells showed that merlin associates with erbB2. This association was further tested in a direct in vitro protein-protein binding assay, which showed that merlin binds directly to erbB2. This data places merlin in the erbB2 signaling pathway.

No description available.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 5 uppsatser.

Neurofibromatosis Type 1 (NF1, von Recklinghausen’s disease) is among the more common autosomal dominant genetic disorders, with a worldwide incidence of approximately 1 in 3000 live births. NF1 can occur as either an inherited defect or as a spontaneous “de novo” mutation. NFI is caused by mutation of the neurofibromin gene that leads to a lack of neurofibromin in the cytoplasm of the cell. Neurofibromin, among other cytoplasmic roles, is a key regulator of certain cellular growth pathways. There is currently no cure for NF1. The disorder has an almost 100% penetrance, but is widely variable in its manifestation. NF1 is a progressive multisystem disorder, and the clinical manifestations tend to worsen with advancing age. NF1 typically manifests as multiple benign skin tumors (neurofibromas), café-au-lait spots, axillary freckles, optical nerve gliomas, iris hamartomas (Lisch nodules), learning disabilities, speech impairment, and orthopedic and cardiovascular problems. More severe manifestations can cause vision loss, headaches, seizures, chronic pain, and orthopedic problems limiting physical activity. Patients with NF1 are four times more likely to develop malignancies than the general population. Several studies have shown that NF1 impairs the patient’s quality of life through association with more severe complications, impacts on the patient’s appearance, and through learning disabilities and depression. In both mild and severe cases, there seemed to be an equal emotional impact on the patient. The psychosocial impact manifests in various ways, including loss of confidence and self-esteem. This can stem from insecurity due to an underlying learning disability or insecurity due to NF1-related cosmetic damage. The academic and emotional damage that follow the learning disability or the lack of confidence, if not treated with appropriate therapy, can go on to impact the patient’s relationships and career. The patient may suffer from social exclusion, financial hardship and inability to obtain health insurance. Patients may be unwilling to have children out of fear of passing on the mutation. This thesis seeks to present in detail the impacts on quality of life that neurofibromatosis causes, and discuss current management and treatment strategies that exist and what can be done further to improve these people’s lives. Early individualized treatment is necessary to achieve better outcomes. Support groups can help educate NF1 patients and their family members and may help alleviate stress. Widespread public education about the condition would help remove the public stigma of Nf1, and allow for patients to feel normal and valued in society. Early individualized treatment is necessary to achieve better outcomes.

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 164-183). Also available on the Internet.