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NF1NF1NeurofibromatosisNeurofibromatosis
Presented by:Presented by:
Jacqueline HoltJacqueline Holt
March 4March 4thth 2003 2003
ObjectivesObjectives
Identity NF1 geneIdentity NF1 gene Biochemistry of NF1Biochemistry of NF1 Mutations in NF1Mutations in NF1 NF1 and cancer (Neurofibromatosis)NF1 and cancer (Neurofibromatosis)
Identity NF1 geneIdentity NF1 gene
NF1 expressed in all tissues of NF1 expressed in all tissues of human, rat, mouse; higher in human, rat, mouse; higher in nervous tissuesnervous tissues
Encodes a protein Neurofibromin Encodes a protein Neurofibromin made of 2839 amino acids; 220kDmade of 2839 amino acids; 220kD
Biochemistry NF1Biochemistry NF1
Neurofibromin- most abundant in Neurofibromin- most abundant in nervous systemnervous system
Large and complex signaling proteinLarge and complex signaling protein
Tumor Suppressor in nervous systemTumor Suppressor in nervous system
Biochemistry of NF1Biochemistry of NF1
Contains a functional GAP-related domain Contains a functional GAP-related domain (GRD)(GRD)
Biochemistry of NF1Biochemistry of NF1
Homologous to the Homologous to the GTPase activating GTPase activating protein (GAP) protein (GAP) family member: family member: p120rasp120ras
GAP proteins turn GAP proteins turn off the ras signal off the ras signal by converting GTP by converting GTP (active) to GDP (active) to GDP (inactive)(inactive)
RAS PathwayRAS Pathway
Ras regulates Ras regulates proliferation and proliferation and differentiationdifferentiation
NF1 PathwayNF1 Pathway
NF1 appears to be NF1 appears to be a negative a negative regulator of the regulator of the RAS signal RAS signal transduction transduction pathway via its pathway via its GAP activity GAP activity domain domain
Tumor suppressorTumor suppressor
NF1 Knockout MiceNF1 Knockout Mice
NF1 heterozygous (NF1 NF1 heterozygous (NF1 +/-+/-) are viable, ) are viable, but develop malignancies; myeloid but develop malignancies; myeloid leukemia leukemia
Homozygous (NF1 Homozygous (NF1 -/--/-) died with heart ) died with heart defectsdefects
Helped with characterization of NF1 Helped with characterization of NF1 function in cell types that are function in cell types that are affected in NF1 tumorsaffected in NF1 tumors
Mutations in NF1Mutations in NF1
Mutation in one copy is enough to Mutation in one copy is enough to produce benign tumors and other produce benign tumors and other symptomssymptoms subcutaneoussubcutaneous
Need mutation in both copies of Need mutation in both copies of alleles to form malignant tumorsalleles to form malignant tumors MPNST (malignant peripheral nerve MPNST (malignant peripheral nerve
sheath tumor)sheath tumor)
Mutations in NF1Mutations in NF1
Examination of NF1 malignant tumor cell Examination of NF1 malignant tumor cell lines showed a decrease or absence of lines showed a decrease or absence of neurofibromin expressionneurofibromin expression
Loss of function results in deregulation of Loss of function results in deregulation of Ras activityRas activity
Results in high levels of active Ras-GTPResults in high levels of active Ras-GTP Results in increase in cell proliferationResults in increase in cell proliferation Schwann cells are primary target for Schwann cells are primary target for
mutationmutation
Test Test NeurofibrominNeurofibromin Activity in a Cell! Activity in a Cell!
NF1 and p16NF1 and p16
p16 is a CDKI; prevents cyclinD binding to p16 is a CDKI; prevents cyclinD binding to cdk4cdk4
Analyzed cells with malignant and benign Analyzed cells with malignant and benign peripheral nerve tumorsperipheral nerve tumors
Found that benign tumors did not have p16 Found that benign tumors did not have p16 deletionsdeletions
Malignant tumors had p16 deletionMalignant tumors had p16 deletion Malignant tumors associate with p16 Malignant tumors associate with p16
deletiondeletion
NF1 & NeurofibromatosisNF1 & Neurofibromatosis
Identified by Friedrich Recklinghausen 1882Identified by Friedrich Recklinghausen 1882 Most common inherited neurological diseaseMost common inherited neurological disease
Autosomal dominantAutosomal dominant 1 in 3,500- 4,0001 in 3,500- 4,000
50% cases are spontaneous50% cases are spontaneous 1 in 10,0001 in 10,000
Primarily affects the development and growth Primarily affects the development and growth of cells in nervous systemof cells in nervous system
NF1 & NeurofibromatosisNF1 & Neurofibromatosis
2 major manifestations:2 major manifestations:
Neurofibromas and gliomas- benign Neurofibromas and gliomas- benign tumors along peripheral and optic tumors along peripheral and optic nerves nerves
NeurofibromasNeurofibromas
Contain 4 cell typesContain 4 cell types Schwann cellsSchwann cells NeuronsNeurons FibroblastsFibroblasts PerineurialPerineurial
3 kinds of Tumors3 kinds of Tumors Cutaneous Cutaneous Interneural Interneural PlexiformPlexiform
Café-au-lait spotsCafé-au-lait spots
11stst symptoms of symptoms of NF1NF1 Important for Important for
diagnosisdiagnosis BenignBenign
Other symptoms include:Other symptoms include: Lisch nodulesLisch nodules Short statureShort stature SeizuresSeizures Learning and behavior dysfunctionLearning and behavior dysfunction Juvenile myeloid leukemiaJuvenile myeloid leukemia Defects in bone structureDefects in bone structure
Other symptoms include:Other symptoms include: Lisch nodulesLisch nodules Short statureShort stature SeizuresSeizures Learning and behavior dysfunctionLearning and behavior dysfunction Juvenile myeloid leukemiaJuvenile myeloid leukemia Defects in bone structureDefects in bone structure
Life expectancy 10-Life expectancy 10-15 years15 years
Malignancy most Malignancy most common cause of common cause of deathdeath
Treatments:Treatments: Laser removal of Laser removal of
neurofibromasneurofibromas Back braces or Back braces or
surgerysurgery Educational Educational
interventionintervention RadiationRadiation ChemotherapyChemotherapy