1. Presented by: Jacqueline Holt March 4th 2003
NF1 Neurofibromatosis
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 3 kinds of Tumors 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