NF1 Neurofibromatosis

1. NF1Neurofibromatosis Presented by: Jacqueline Holt March 4th 2003

2. Objectives • Identity NF1 gene • Biochemistry of NF1 • Mutations in NF1 • NF1 and cancer (Neurofibromatosis)

3. Located on chromosome 17q11.2

4. Identity NF1 gene • NF1 expressed in all tissues of human, rat, mouse; higher in nervous tissues • Encodes a protein Neurofibromin made of 2839 amino acids; 220kD

5. Biochemistry NF1 • Neurofibromin- most abundant in nervous system • Large and complex signaling protein • Tumor Suppressor in nervous system

6. Biochemistry of NF1 Contains a functional GAP-related domain (GRD)

7. Biochemistry of NF1 • Homologous to the GTPase activating protein (GAP) family member: p120ras • GAP proteins turn off the ras signal by converting GTP (active) to GDP (inactive)

8. RAS Pathway • Ras regulates proliferation and differentiation

9. NF1 Pathway • NF1 appears to be a negative regulator of the RAS signal transduction pathway via its GAP activity domain • Tumor suppressor

10. NF1 Knockout Mice • NF1 heterozygous (NF1 +/-) are viable, but develop malignancies; myeloid leukemia • Homozygous (NF1 -/-) died with heart defects • Helped with characterization of NF1 function in cell types that are affected in NF1 tumors

11. Mutations in NF1 • Mutation in one copy is enough to produce benign tumors and other symptoms • subcutaneous • Need mutation in both copies of alleles to form malignant tumors • MPNST (malignant peripheral nerve sheath tumor)

12. Mutations in NF1 • Examination of NF1 malignant tumor cell lines showed a decrease or absence of neurofibromin expression • Loss of function results in deregulation of Ras activity • Results in high levels of active Ras-GTP • Results in increase in cell proliferation • Schwann cells are primary target for mutation

13. Test Neurofibromin Activity in a Cell!

14. NF1 and p16 • p16 is a CDKI; prevents cyclinD binding to cdk4 • Analyzed cells with malignant and benign peripheral nerve tumors • Found that benign tumors did not have p16 deletions • Malignant tumors had p16 deletion • Malignant tumors associate with p16 deletion

15. NF1 & Neurofibromatosis Identified by Friedrich Recklinghausen 1882 Most common inherited neurological disease Autosomal dominant 1 in 3,500- 4,000 50% cases are spontaneous 1 in 10,000 Primarily affects the development and growth of cells in nervous system

16. NF1 & Neurofibromatosis • 2 major manifestations: • Neurofibromas and gliomas- benign tumors along peripheral and optic nerves

17. Neurofibromas • Contain 4 cell types • Schwann cells • Neurons • Fibroblasts • Perineurial • 3 kinds of Tumors • Cutaneous • Interneural • Plexiform

18. Café-au-lait spots • 1st symptoms of NF1 • Important for diagnosis • Benign

19. Other symptoms include: • Lisch nodules • Short stature • Seizures • Learning and behavior dysfunction • Juvenile myeloid leukemia • Defects in bone structure

21. Other symptoms include: • Lisch nodules • Short stature • Seizures • Learning and behavior dysfunction • Juvenile myeloid leukemia • Defects in bone structure

23. Life expectancy 10-15 years • Malignancy most common cause of death • Treatments: • Laser removal of neurofibromas • Back braces or surgery • Educational intervention • Radiation • Chemotherapy