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
www.science.room.net/.../Neurofibromotosis/
 Bony defects
 Tumors of the central nervous system.

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_muta
tionen.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
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?

1. Ras GTPase Activator Activity

2. Adenylate cyclase and cAMP
3. AKT-mTOR mediated pathways
4. 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?b
ook=gene&part=nf1
 http://www.upmc.edu/Neurofibro/NNFFconsortiu
m.htm
 http://www.genetests.org/query?gene=NF1
 http://egp.gs.washington.edu/data/nf1/
 http://herkules.oulu.fi/isbn9514268040/html/i100
0977.html
 http://www.ncbi.nlm.nih.gov/pubmed/2114220?d
opt=Abstract&holding=npg