Neurofibromatosis Type I (NF1) Presented by Lei Du

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

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. www.science.room.net/.../Neurofibromotosis/ Variation in clinical features both inter and intra-familially

Genetic Info: Cloned in 1990 using overlapping cDNA clones from the translocation breakpoint region (TBR) gene Encodes Neurofibromin 1 on Chromosome 17 http://ghr.nlm.nih.gov/dynamicImages/chromomap/nf1.jpeg

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

More than 1000 NF1 mutations has been identified Single nucleotide substitutions Minor molecular lesions Large-scale genomic deletions Chromosomal instability http://www.tuxhausen.de/pic/ms_linux_pinguin_mutationen.jpg

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 http://news.bbc.co.uk/hi/english/static/in_depth/sci_tech/2000/human_genome/default.stm

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 http://www.wildlifetrust.org.uk/cheshire/IMAGES/watch_harvest_mice.jpg

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

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

Active Ras promote cell proliferation  Tumor http://219.221.200.61/ywwy/zbsw(E)/edetail6.htm

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!!! http://farm1.static.flickr.com/31/54275159_1a756047cf.jpg

NF1

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

NF1: Lee & Stephenson (2007)

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.

Reference: http://www.genecards.org/cgi-bin/carddisp.pl?gene=NF1 http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=nf1 http://www.upmc.edu/Neurofibro/NNFFconsortium.htm http://www.genetests.org/query?gene=NF1 http://egp.gs.washington.edu/data/nf1/ http://herkules.oulu.fi/isbn9514268040/html/i1000977.html http://www.ncbi.nlm.nih.gov/pubmed/2114220?dopt=Abstract&holding=npg

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