Presented by: Jacqueline Holt March 4th 2003 NF1 Neurofibromatosis Presented by: Jacqueline Holt March 4th 2003

Objectives Identity NF1 gene Biochemistry of NF1 Mutations in NF1 NF1 and cancer (Neurofibromatosis)

Located on chromosome 17q11.2

Identity NF1 gene NF1 expressed in all tissues of human, rat, mouse; higher in nervous tissues Encodes a protein Neurofibromin made of 2839 amino acids; 220kD

Biochemistry NF1 Neurofibromin- most abundant in nervous system Large and complex signaling protein Tumor Suppressor in nervous system

Biochemistry of NF1 Contains a functional GAP-related domain (GRD)

Biochemistry of NF1 Homologous to the GTPase activating protein (GAP) family member: p120ras GAP proteins turn off the ras signal by converting GTP (active) to GDP (inactive)

RAS Pathway Ras regulates proliferation and differentiation

NF1 Pathway NF1 appears to be a negative regulator of the RAS signal transduction pathway via its GAP activity domain Tumor suppressor

NF1 Knockout Mice NF1 heterozygous (NF1 +/-) are viable, but develop malignancies; myeloid leukemia Homozygous (NF1 -/-) died with heart defects Helped with characterization of NF1 function in cell types that are affected in NF1 tumors

Mutations in NF1 Mutation in one copy is enough to produce benign tumors and other symptoms subcutaneous Need mutation in both copies of alleles to form malignant tumors MPNST (malignant peripheral nerve sheath tumor)

Mutations in NF1 Examination of NF1 malignant tumor cell lines showed a decrease or absence of neurofibromin expression Loss of function results in deregulation of Ras activity Results in high levels of active Ras-GTP Results in increase in cell proliferation Schwann cells are primary target for mutation

Test Neurofibromin Activity in a Cell!

NF1 and p16 p16 is a CDKI; prevents cyclinD binding to cdk4 Analyzed cells with malignant and benign peripheral nerve tumors Found that benign tumors did not have p16 deletions Malignant tumors had p16 deletion Malignant tumors associate with p16 deletion

NF1 & Neurofibromatosis Identified by Friedrich Recklinghausen 1882 Most common inherited neurological disease Autosomal dominant 1 in 3,500- 4,000 50% cases are spontaneous 1 in 10,000 Primarily affects the development and growth of cells in nervous system

NF1 & Neurofibromatosis 2 major manifestations: Neurofibromas and gliomas- benign tumors along peripheral and optic nerves

Neurofibromas Contain 4 cell types 3 kinds of Tumors Schwann cells Neurons Fibroblasts Perineurial 3 kinds of Tumors Cutaneous Interneural Plexiform

Café-au-lait spots 1st symptoms of NF1 Important for diagnosis Benign

Other symptoms include: Lisch nodules Short stature Seizures Learning and behavior dysfunction Juvenile myeloid leukemia Defects in bone structure

Other symptoms include: Lisch nodules Short stature Seizures Learning and behavior dysfunction Juvenile myeloid leukemia Defects in bone structure

Life expectancy 10-15 years Malignancy most common cause of death Treatments: Laser removal of neurofibromas Back braces or surgery Educational intervention Radiation Chemotherapy