Neurofibromatosis 1 Neurofibromatosis 1

von von RecklinghausenRecklinghausen SyndromeSyndrome

Kristin Neitzke Kristin Neitzke

Huang Chunsaihttp://www.youtube.com/watch?v=xeJBdeNd1x0&feature=related

What is it?What is it?

Inherited disorder affecting nervous systemInherited disorder affecting nervous system

Affects 1 in 3,500 worldwide usually childrenAffects 1 in 3,500 worldwide usually children

~50% of cases inherited, 50% sporadic~50% of cases inherited, 50% sporadic

Symptoms of NF1Symptoms of NF1

• Symptoms begin Symptoms begin between birth and between birth and age 10age 10

http://webhome.idirect.com/~nfso/symptoms.jpg

Most Common SymptomsMost Common Symptoms

Café-au-lait Spots

http://www.science.room.net/geneticdisordersimages/Neurofibromotosis/cafe%20au%20Lait%20spots%20neuofib.jpg

Lisch Nodules

http://cc.oulu.fi/~anatwww/NF/Neurofibromatosis/lisch.gif

The NF1 Gene is LargeThe NF1 Gene is Largeand Highly Mutableand Highly Mutable

http://images.google.com/imgres?imgurl=http://herkules.oulu

NF1 Encodes NeurofibrominNF1 Encodes Neurofibromin

• Cytoplasmic ProteinCytoplasmic Protein• Tumor SuppressorTumor Suppressor

http://en.wikipedia.org/wiki/Neurofibromin_1

Gangfeng, 1990

NeurofibrominNeurofibromin

• Tumor suppressorTumor suppressor• Cytoplasmic proteinCytoplasmic protein• Has homology with Has homology with

RAS-GTPase RAS-GTPase activating protein activating protein (GAP) in mammals(GAP) in mammals

http://en.wikipedia.org/wiki/Neurofibromin_1

Gangfeng, 1990

How GAP FunctionsHow GAP Functions

http://www.wormbook.org/chapters/www_RTKRasMAPKsignaling/rtkrasfig3.jpg

How Does Neurofibromin Work?How Does Neurofibromin Work?

http://cc.oulu.fi/~anatwww/NF/Neurofibromin/Ras.jpg

How Does Neurofibromin Work?How Does Neurofibromin Work?

http://cc.oulu.fi/~anatwww/NF/Neurofibromin/Ras.jpg

NF1 in Other Signaling PathwaysNF1 in Other Signaling Pathways

http://www.nature.com/ng/journal/v27/n4/fig_tab/ng0401_354_F1.html

Knockout Mice Have Heart DefectsKnockout Mice Have Heart Defects

Double Outlet Right VentricleNormal Heart

Jacks, et al. 1994

Heterozygous Mutant MiceHeterozygous Mutant Miceare Predisposed to Tumorsare Predisposed to Tumors

Survival curve of a population of 52 +/+ and 40 +/- animals

Tumors were observed in 8 +/+ and 30+/- animals

How does loss of NF1 promote How does loss of NF1 promote tumor formation?tumor formation?

• Loss of neurofibromin in Schwann cell Loss of neurofibromin in Schwann cell leads to tumorigenesisleads to tumorigenesis

• LOH is observed in pheochromocytomas LOH is observed in pheochromocytomas and myeloid leukemiasand myeloid leukemias

How does loss of NF1 promote How does loss of NF1 promote tumor formation?tumor formation?

• Plexiform neurofibromas can become Plexiform neurofibromas can become malignant tumors (5% of cases)malignant tumors (5% of cases)

• These often have loss of p53 and These often have loss of p53 and mutations in INK4 (p16 and Arf)mutations in INK4 (p16 and Arf)

Therapies for NF1Therapies for NF1

• Cochlear Implantation• Lovastatin• Drug Therapy (Chemotherapy)• Traction

SourcesSources• Upadhyaya M. 1998. "Gross Deletions of the Neurofibromatosis Type 1 (NF1) Gene Upadhyaya M. 1998. "Gross Deletions of the Neurofibromatosis Type 1 (NF1) Gene

are Predominantly of Maternal Origin and Commonly Associated with a Learning are Predominantly of Maternal Origin and Commonly Associated with a Learning Disability, Dysmorphic Features and Developmental Delay.". Human Genetics Disability, Dysmorphic Features and Developmental Delay.". Human Genetics 102:591-7.102:591-7.

• Yuan Z. 2008 [cited 2008 Mar 26]. Nature Genetics. [Internet]. University of Texas. Yuan Z. 2008 [cited 2008 Mar 26]. Nature Genetics. [Internet]. University of Texas. Available from: Available from: <http://images.google.com/imgres?imgurl=http://www.nature.com>. <http://images.google.com/imgres?imgurl=http://www.nature.com>.

• Jacks T, Shih S, Earlene S. 1994. Tumour predisposition in mice heterozygous for a Jacks T, Shih S, Earlene S. 1994. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nature 7:353-61.targeted mutation in Nf1. Nature 7:353-61.

• Dasgupta B, Gutmann D. 2003. Neurofibromatosis 1: Closing the GAP between mice Dasgupta B, Gutmann D. 2003. Neurofibromatosis 1: Closing the GAP between mice and men. Current Opinion in Genetics and Development 13:20-7. and men. Current Opinion in Genetics and Development 13:20-7.

• http://herkules.oulu.fi/isbn9514266463/html/x312.html• http://www.understandingnf1.org/exp/int_exp_wci.html• http://www.nfincne.org/uploads/documents/testimony.pdf• http://herkules.oulu.fi/isbn9514271106/html/x239.html• http://www.curehunter.com/public/keywordSummaryD009456.do• http://www.sciencedirect.com/science? • http://www.understandingnf1.org/exp/int_exp_wci.html• http://www.curehunter.com/public/keywordSummaryD009456.do