Neurofibromatosis Type I (NF1)

Slides:



Advertisements
Similar presentations
The Patterns of Genetic Inheritance By Dr. Joann Boughman, PhD Autosomal Dominant Autosomal Recessive X-linked Recessive X-linked Dominant Y-linked Imprinting.
Advertisements

Neurofibromatosis Type 1 (NF1) Von Recklinghausen Disease
Neurofibromatosis (NF)
Neurofibromatosis and Seizures “Knowledge is Power”
Chapter 19 Lecture Concepts of Genetics Tenth Edition Cancer and Regulation of the Cell Cycle.
Cancer: a genetic disease of inherited and somatic mutations n Gene mutations and/or genetic instability are involved in many cancers. n Viruses and environmental.
NF2/Merlin and Neurofibromatosis 2
SELECTED TOPICS IN GENETIC DISORDERS.
Retinoblastoma by Michele Chasteen What is Retinoblastoma? n n Tumor of the eye that can occur at a high frequency in children and sporadically at an.
TSC2 and Tuberous Sclerosis Complex Disease Laura Koontz Biology 169.
Presented by: Jacqueline Holt March 4th 2003
NF2: A Tumor Suppressor NF2 encodes Merlin/Schwannomin, a protein that regulates cell growth and proliferation.
MSH2 and Human Nonpolyposis Colon Cancer Yael Aschner.
SMAD4/DPC4: A Tumor Suppressor James Brooks March 23 rd, 2006.
The genetic basis for the development of cancer
Autosomal Dominant Disorders
Neurofibromatosis 1 von Recklinghausen Syndrome Kristin Neitzke.
BRCA2 Blue: Rad51; Green: BRCA2
Neurofibromatosis (NF) aka “von Recklinghausen disease” Brennan Coffey Logan Ernst Period 3.
Neurofibromatosis By Katelynn Johnson and Katie Duvall.
Protein Synthesis Mutations and Genetic Disorders.
DR. ERNEST K. ADJEI FRCPath. DEPARTMENT OF PATHOLOGY SMS-KATH
CLINICAL GENETICS (MTD-356)
N EUROFIBROMATOSIS (NF) By Angela M. O VERVIEW Discovered by Friedrich Daniel von Recklinghausen in 1882 Genetic neurological disorder that affects cell.
Cancer --an Overview  Cell Division  Hormones and Cancer  Malignant Transformation  Angiogenesis and Metastasis  Growth.
 More than half of Mendelian phenotypes are autosomal dominant  Examples:  Familial hypercholesterolemia  Myotonic dystrophy  Huntington disease 
Chap. 5 Problem 1 Recessive mutations must be present in two copies (homozygous) in diploid organisms to show a phenotype (Fig. 5.2). These mutations show.
Neurofibromatosis Ben Saward ST3 VTS February 2012.
Neurofibromatosis type 1. Biallelic NF1 inactivation leads to multiple symptoms.
Mutations.
TSC1 and Facial Angiofibromas
Tumor Suppressors Versus Oncogenes. Retinoblastoma is a Cancerous Disease Hereditary childhood cancer: bilateral tumors in 25-30% of cases unilateral.
Neurofibromatosis 1- NF1 BIOL 445 Alexa Schulman Gutmann et al
NF1 (Neurofibromatosis Type 1) Greg Hogan Ribbon Representation of NF1-333 Scheffzek, et al. (The EMBO Journal Vol. 17,pp , 1998) Structural.
„Café-au-lait”- Spots Dr. György Fekete II. Department of Pediatrics Semmelweis University, Budapest.
TSC1/Hamartin and Facial Angiofibromas Biology 169 Ann Hau.
GENETICS Dr. Samar Saleh Assiss. Lecturer Mosul Medical College Pathology3 rd year.
Gene Expression and Retinoblastoma “Cancer of the Eye”
Fig 1a Fig 1b Fig 2a Fig 2b History: 52 year old female presents with a palpable mass. A two part diagnosis must be given to be considered a correct.
RARE OCULAR MANIFESTATION OF NEUROFIBRAMATOSIS TYPE 1
GENETIC BASIS OF CANCER
Chapter Seven: Extending Mendelian Genetics
Neurofibromatosis 1 Valerie Khodush March 27, 2007
The Genetic Basis of Cancer
NEUROFIBROMATOSIS noo r-oh-fahy-broh-muh-toh-sis
Neurofibromatosis type 1
The Patterns of Genetic Inheritance
Cancer as a genetic disease
NF2/Merlin Michael Anderson.
Mutations TSW identify and describe the various types of mutations and their effects.
What makes a mutant?.
Retinoblastoma and the Rb1 Gene
Tuberous Sclerosis TSC2/ Tuberin Alison Chappell.
TSC1 in Facial Angiofibromas
TSC2 GENE ENCODES FOR TUBERIN
Genetics Of Cancer Regulation of cell proliferation and cancer
Chapter 17: Regulation of cell number
Colorectal cancer : Three pathways
PTEN (a.k.a. MMAC1 and TEP1) and Cowden’s Disease
Extracellular Regulation of Apoptosis
The Patterns of Genetic Inheritance By Dr. Joann Boughman, PhD Autosomal Dominant Autosomal Recessive X-linked Recessive X-linked Dominant Y-linked Imprinting.
PTEN Tumor Suppressor and Cancer
BMP Receptor 1a and Juvenile Polyposis Syndrome
Genetics and Molecular diagnosis of Genodermatosis
Cancer Lecture 42 BSCI 420,421,620 Dec 11, 2002
Neurofibromatosis Eldar Kurtovic School of Engineering
NF1 Tumor Suppressor Gene Function
Presentation transcript:

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

Questions?