1. Neurofibromatosis Type I (NF1)
Presented by Lei Du

2. What is Neurofibromatosis Type I?
a hereditary neurological disorder
affects 1 in 3,000 people world-wide
Autosomal dominant with fully penetrant
Caused by mutation in NF1 gene, codes for neurofibromin 1
2-hit Hypothesis
30~50% arises from sporadic mutations
A common cancer-predisposing disease

3. NF1 affects a variety of tissues
Café-au-lait spots
Lisch nodules in iris
Skin Neurofibroma
Plexiform neurofibroma
Bony defects
Tumors of the central nervous system.
Variation in clinical features both inter and intra-familially

4. Genetic Info:
Cloned in 1990 using overlapping cDNA clones from the translocation breakpoint region (TBR) gene
Encodes Neurofibromin 1
on Chromosome 17

5. Mutation rate is one of the highest of human disease genes
Size: 2839 Amino Acid
By comparison:
Estimated average: ~300
Rb gene: 928
Ras gene: 1047
www. wikimedia.org

6. More than 1000 NF1 mutations has been identified
Single nucleotide substitutions
Minor molecular lesions
Large-scale genomic deletions
Chromosomal instability

7. Where is NF1 expressed?
Ubiquitously expressed in a range of tissues such as bone and skin
Greatest in cells with a neurological origin: schwann cells, neurons
Also in karatinocytes and melanocytes

8. Animal Model: Mice Homozygous die
Yang et al. (2006)
NF1 acts in the Ras pathway!!!
Homozygous die
+/- fibroblasts increased proliferation, migration, and collagen synthesis
-/- cells develop neurofibromas
mice that carry linked germline mutations in Nf1 and p53 develop malignant peripheral nerve sheath tumors

9. In Ras Pathway:
Lodish et al. Fig. 20-5

10. Neurofibromin contains domain resembles GAP
Encodes for a TUMOR SUPPRESSOR
Lodish et al. Fig. 20-5

11. Active Ras promote cell proliferation  Tumor

12. Animal Model: Drosophila
In Drosophila (Tong et al, 2007)
Inactivation of NF1
reduced life span and reproductive fitness
increased vulnerability to heat
reduced mitochondrial respiration
Over-expression of NF1 Opposite result
NF1 acts in the Adenylate Cyclase and cAMP pathway!!!

13. NF1

14. What is the function of NF1?
Ras GTPase Activator Activity
Adenylate cyclase and cAMP
AKT-mTOR mediated pathways
PKC pathway Cell mobility

15. NF1: Lee & Stephenson (2007)

16. Summary:
Neurofibramatosis Type 1 is a hereditary neurocutaneous disorder that affects a variety of tissue types
NF1 gene product is a tumor suppressor
Mutation in both copies has cancer pre-disposing function
It acts in many pathways: Ras, cAMP, PKC, & mTOR
phenotypically dominant with full penetrant.

17. Reference: http://www.genecards.org/cgi-bin/carddisp.pl?gene=NF1

18. Questions?