Genetic conditions Autosomal Dominant Achondroplasia FGFR3 Inhibition of chondrocytes proliferation Apert Syndrome FGFR2 Inhibition of chondrocytes proliferation CMT (80-90%) PMP22 Nerve demyelination Pseudoachondroplasia COMP Abnormal cartilage formation SED congenita COL2A1 / Type II collagen Defect in cartilage matrix formation Kniest Dysplasia COL2A1 / Type II collagen Defect in cartilage matrix formation MED - Type I COMP Type II collagen MED - Type II Type IX collagen Type IX collagen Jansen's metaphyseal chondrodysplasia PTHrP Functional defect in parathyroid hormone Schmid's metaphyseal chondrodysplasia Type X Collagen Defect in cartilage matrix formation Cleidocranial dysplasia RUNX2/CBFA1 Impaired intramembranous ossification Osteogenesis Imperfecta (Type I, II, III, IV, V) COL1A1/COL1A2 Type I collagen Autosomal Recessive Diastophic dysplasia DTD (Sulfate Transport Protein) Defect in sulfaction of proteoglycan Friedreich Ataxia Frataxin Osteogenesis Imperfecta (Type VI) SERPINF1 McKusick metaphyseal chondrodysplasia RMRP gene X-Linked Recessive SED tarda TRAPPC2 gene Type II collagen CMT (10-20%) Connexin gene Nerve demyelination Epigenetics Overview epigenetic changes include inheritable genetic alteration (developmental or environmental cues) that do NOT involve DNA mutation DNA methylation, histone modification, nucleosome location, or noncoding RNA are components of epigenetics osteoarthritis is thought to have epigenetic mechanisms that influence the disease process Translocations Overview translocations allow expression of genes (oncogenes) that are usually not active. cytogenetic analysis allows for the detection of gene translocations by evaluating the size and number of chromosomes isolated from the cell nucleus. Examples present in up to 95% of sarcomas. Translocations Disease Translocation Gene Ewing's sarcoma t (11:22) Fusion protein (EWS-FLI1) Rhabdomyosarcoma t (2:13) Pax3-FKHR Myxoid liposarcoma t (12:16) TLS-CHOP Synovial sarcoma t (X:18) SYT-SSX1, 2, or 4 fusion protein Clear cell sarcoma t (12:22) Fusion protein EWS-ATF1 Chondrosarcoma (Myxoid Variant) t (9:22) Fusion protein EWS-CHN Tumor Suppressor Genes Definition inhibit cell proliferation therefore a mutation interfering with normal function causes leads to uncontrolled cell growth Examples retinoblastoma protein (pRB-1) acts as a regulator of gene expression recessive suppressor both alleles must be mutated to have uncontrolled growth Rb mutation in 100% of retinoblastomas 35% of osteosarcomas abnormal state is phosphorylated and unable to bind to DNA to regulate p53 normal protein prevents entrance into S-phase of cell cycle when DNA is damaged dominant suppressor single allele must be mutated to have uncontrolled growth mutation in this gene found in 50% of all tumors osteosarcoma (20-65%) chondrosarcoma Li-Fraumeni syndrome Oncogenes Definition induce uncontrolled growth normal function causes leads to uncontrolled cell Examples FAK focal adhesion kinase Erb-2 epidermal growth factor variant Tumor Antigens Definition tumor antigens are used in the diagnosis, monitoring of treatment response, and are being researched for treatment options as anti-cancer vaccines Examples carcinoembryonic antigen (CEA) colorectal carcinoma carbohydrate antigen 19-9 (CA-19-9) pancreatic cancer carbohydrate antigen 125 (CA-125) ovarian cancer cancer antigen 15-3 (CA-15-3) breast cancer alpha fetoprotein (AFP) can be seen in many cancers, but is most commonly seen in hepatocellular carcinomas Assays Western blot detects protein Southern blot detects DNA Northern blot detects RNA Southwestern blot detects DNA binding proteins RT-PCR reverse transcription PCR highly sensitive, detects low copy number of RNA reversed transcribed into complimentary DNA (cDNA) may be used together with Northern blot siRNA small interfering RNA; blocks translation of mRNA useful for loss-of-function experiment designs