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Neurofibromatosis Type 1: Piecing the Puzzle Together

Published online by Cambridge University Press:  18 September 2015

Matthias M. Feldkamp ,
David H. Gutmann  and
Abhijit Guha
Matthias M. Feldkamp
Affiliation:
Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto Division of Neurosurgery, The Toronto Hospital, and University of Toronto, Toronto, U.S.A.
David H. Gutmann
Affiliation:
Departments of Neurology and Genetics, Washington University School of Medicine, St. Louis, U.S.A.
Abhijit Guha*
Affiliation:
Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto Division of Neurosurgery, The Toronto Hospital, and University of Toronto, Toronto, U.S.A. Department of Surgical Oncology, Ontario Cancer Institute, Peripheral Nerve Unit, The Toronto Hospital, Toronto, Ontario.
*
2-415 McLaughlin Pavilion, The Toronto Hospital, Toronto Western Division, 399 Bathurst Street Toronto, Ontario, Canada M5T 2S8
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Abstract:

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Neurofibromatosis type 1 (NF1) was first described in 1882 and is characterized by a diverse spectrum of clinical manifestations, including neurofibromas, cafe au lait spots, and Lisch nodules. NF1 is also noted for the higher risk of associated malignancies, making it the most common tumour-predisposing disease in humans. Transmitted in an autosomal dominant manner, the NFI gene was cloned in 1990, and belongs to the family of tumour suppressor genes. Since then, there has been an explosion in our understanding of how the gene product, neurofibromin, functions in normal cellular physiology, and how its loss in NF1 relates to the wide spectrum of clinical findings, including NF1-associated tumours. Neurofibromin is a major negative regulator of a key signal transduction pathway in cells, the Ras pathway, which transmits mitogenic signals to the nucleus. Loss of neurofibromin leads to increased levels of activated Ras (bound to GTP), and thus increased downstream mitogenic signaling. Our understanding of neurofibromin's role within cells has allowed for the development of pharmacological therapies which target the specific molecular abnormalities in NF1 tumours. These include the farnesyl transferase inhibitors, which inhibit the post-translational modification of Ras, and other agents which modulate Ras-mediated signaling pathways.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 25 , Issue 3 , August 1998 , pp. 181 - 191
Copyright
Copyright © Canadian Neurological Sciences Federation 1998

References

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