Genetics: Genetic Testing, Genomics, Gene Therapy – Flashcards
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Are there tests available for Mendelian traits?
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Yes
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Are there tests available for Multi-factorial traits?
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Yes
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What multi-factorial conditions have tests available for them?
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Breast cancer, ovarian cancer, colon cancer
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Neurofibromatosis type 1 affects what?
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The peripheral nervous system
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What type of inheritance is Neurofibromatosis type 1?
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Autosomal dominant
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Where is the gene locus that is affected in people with Neurofibromatosis type 1?
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Chromosome 17q11
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What is the mutations that causes neurofibromatosis type 1?
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NF1 gene
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What is the product of the NF1 gene?
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neurofibromin
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What is not produced in people with neurofibromatosis type 1?
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Neurofibromin
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Cafe-Au-Alit spots are common to what disease?
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Neurofibromatosis type 1
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What are cafe-au-lait spots?
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Patches of hyper pigmentation
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Characteristics of neurofibromatosis type 1
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Cafe-Au-Alit spots, neurofibromas, lisch nodule
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Lisch nodule
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Small harmatoma in the iris
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Lisch nodule are common to what disease?
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Neurofibromatosis type 1
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What are neurofibromas?
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Nerve sheath neoplasms
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What nerves do the neurofibromas of neurofibromatosis type 1 develop along?
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Peripheral nerve fibers
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What do the neurofibromas of neurofibromatosis type 1 cause?
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Major disfigurement, bone erosion, and damage to peripheral nerves
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Which of the two types of neurofibromatosis is more common?
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Neurofibromatosis type 1
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Neurofibromatosis type 2 affects what?
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Central nervous system
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What is the primary characteristic of Neurofibromatosis type 2?
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Bilateral acoustic neuromas
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What is the result of bilateral acoustic neuromas in neurofibromas type 2 patients?
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Deafness
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Intracranial and paraspinal neoplasms are associated with what disease?
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Neurofibromatosis type 2
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What intracranial and paraspinal neoplasms are associated with neurofibromatosis type 2?
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Meningiomas and gliomas
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What type of inheritance is neurofibromatosis type 2?
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Autosomal dominant
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Where is the gene locus associated with Neurofibromatosis type 2?
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Chromsome 22q11-13
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What gene is mutated in neurofibromatosis type 2?
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NF2
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What does the NF2 gene produce?
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Merlin
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What is not produced in people with neurofibromatosis type 2?
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Merlin
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What type of disease is Huntington chorea?
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A neurodegenerative disorder
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What signs and symptoms characterize Huntington chorea?
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Chorea and dementia
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Chorea
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Jerky body movements
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When is the onset of Huntington disease?
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3rd or 4th decade of life
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What is the inheritance pattern of Huntington disease?
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Autosomal dominant inheritance with complete penetrance
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Complete penetrance
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All who have the gene have the phenotype
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Is there a cure for Huntington Disease?
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No
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What is gene testing useful for?
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Making risk estimates in pre-symptomatic individuals with family members who have the disorder and provide information to help effective disease management by the patient and healthcare provider
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Scientific limitations of gene testing
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May not detect every mutation Detected mutations may present different risks on at the individual and population level Lack of effective treatments and preventive measures for detected conditions
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Genome
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The gene complement of an organism
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Genome sequence comprises what
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The information of the entire genetic material of an organism
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What does genetics study?
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Single genes and their role in heredity
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What is genomics?
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The determination of the complete DNA sequence for all the genes of an organism
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What is the same as functional genomics?
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Functional proteomics
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What is the goal of functional proteomics?
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Determination of proteome function
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Proteome
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All proteins encoded by the genome
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What is the goal of structural genomics
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Determination of complete structure of entire proteome
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What tools are used for structural genomics?
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X-ray crystallography NMR spectroscopy Interpretation of DNA/mRNA sequence
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What is pharmacogenomics moving away from?
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One size fits all therapeutics
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What is the goal of pharmacogenomics?
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To find the correlation between DNA variants and individual responses to medication
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How will pharmocogenomics help in customizing drugs?
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They will be customized for groups of patients that have similar responses to medical treatment
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Adverse responses to drugs kill how many people yearly?
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Over 100,000
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How many people have side effects or no benefit from drugs?
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2 million
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What percent of patients have had an adverse reaction to at least one drug?
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48%
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What does more effective, specific drug use require?
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Correlation between patient's genetic make-up and response to the drug
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Where can pharmacogenomics be applied?
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human gene therapy Protein therapy Drug targets combining chemistry and genetics Drug design
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Associated targets with disease processes and pathways aim at producing what?
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Specifically designed small molecule therapeutics Antibody immunotherapeutics Cellular immunotherapeutics
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Antibody immunotherapeutics include
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Monoclonal antibodies Magic Bullet
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Cellular immunotherapeutics include
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Transfected WBC Dendritic cells
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Single nucleotide polymorphisms
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One amino acid encoded by multiple codons
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What could single nucleotide polymorphisms offer?
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The opportunity for drug adaptation to fit the individual's genetic makeup
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Personalized drugs are supposed to __________________________ and ____________ without _____________________.
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Effective Safely Side effects
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What is the oldest antibody drug?
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Herceptin
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What does Herceptin do?
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Shrinks tumors and prolongs lives
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What is Herceptin prescribed for?
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Metastatic breast cancer when patient's tumors are HER2 (+)
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What percent of patients have HER2?
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30%
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What does Herceptin not work in?
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HER2(-) breast cancer patients
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What must be present for Herceptin to work?
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HER2
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What is Herceptin?
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A monoclonal antibody specific for HER2 antigen
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How does Herceptin shrink tumors?
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It binds to HER2 and slows tumor growth
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Matching drug therapy and disease to patient's genetic profile leads to what?
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Improved drug choice and safer drug as it works the first time and has less likely adverse effects with a faster recovery
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What is drug dosage currently based on?
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weight, age and gender
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How will individuals drug therapy make drug dose more accurate?
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Adding patient's genetics as a major factor for determining drug and dosage will make overdose less likely
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Why will adding a patient's genetics make overdose less likely
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Specific drug processing in the body of the individual and speed of drug metabolism will be taken into account
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What increases the susceptibility to ankylosing spondylitis?
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HLA-B27
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People with HLA-B27 are how much more likely to develop ankylosing spondylitis
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90X
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Current vaccines depend on what?
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Whole killed or attenuated live pathogen
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What vaccines is an attenuated live pathogen?
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OPV polio vaccine
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What do current vaccines do to the immune system
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Challenge the immune system with too many antigens
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What is the better version of vaccines
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DNA
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DNA vaccines do what?
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Elicit immune response specifically for exposed antigens
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What is not caused by DNA vaccines that might be caused by current vaccines?
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Infection or disease
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What do DNA vaccines cover that current vaccines do not?
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Multiple strains of the infectious agent
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How do DNA vaccines cover multiple strains of the infectious agent?
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By combining genes on one plasmid
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How long can DNA vaccines be stored?
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Up to 6 months at room temperature
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Tamoxifen does what?
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Reduces the risk of breast cancer in women with BRCA1 and BRCA2 gene variants
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What do BRCA1 and BRCA2 gene variants do?
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Increase cancer risk
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What is tamoxifen an antagonist for?
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Estrogen receptor in breast tissue
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What is tamoxifen an agonist for?
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Estrogen receptor in endometrium
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What other cancers have similar markers that are potential candidates for prevention using drugs as preventive medicine?
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Prostate and colon cancer
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What is Cytochrome p450 involved in?
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Drug metabolism and detoxification of the body
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What types of drugs can be affected by cytochrome p450
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Psychiatric, neurological and cardiovascular drugs
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How can drugs be individualized when concerning cytochrome p450
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Drug and dosage can be determined and adjusted to the specific p450 gene of the patient
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Gene therapy applications
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Treatment of disease Supporting normal function Treatment of genetic disorders
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Example of gene therapy applications used to treat a disease
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Defective genes can be replaced or supplemented by healthy genes
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How can gene therapy be used to support normal function?
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Through immune response to disease
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What genetic disorders are currently being examined for gene therapy?
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Cancer Metabolic disorders
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How is gene therapy being used to treat cancer?
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By introducing a plasmid into the cell that has a gene to produce IL-2 or B7
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What is the obstacle of gene therapy?
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Safe gene-delivery
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What is the problem with using viruses as vehicles of gene-delivery
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They might revert to pathogenicity
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Examples of X-linked recessive diseases
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Duchenne muscular dystrophy Hemophilia A
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Recurrence risk
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The probability that an affected child will be produced in a family that already has produced at least one affected child
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Who was a carrier of hemophilia that transmitted it amongst royal families?
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Queen victoria
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What can be fatal to hemophiliacs that are not fatal to people without the mutation?
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Minor cuts and bruises
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What do hemophiliacs lack?
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Clotting factors VIII and IX
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Before 1994 what happened to patients with hemophilia during treatment?
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They were treated with clotting proteins contaminated with the AIDS virus and developed HIV/AIDS
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What are hemophiliac's currently treated with?
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genetically engineered proteins
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What does the sickle cell trait protect carriers from?
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Falciparum malaria
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Individuals with 2 copies of the sickle cell gene encode what?
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Defective hemoglobin
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When a person has 1 sickle cell gene and 1 normal gene what is the result
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Unaffected from sickle cell disease and able to resist malaria
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Where is malaria endemic?
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West Africa
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What disease is a likely candidate for Gene therapy?
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Lesch-Nyhan
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What type of disorder is Lesch-Nyhan
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Metabolic disorder
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What is the defect in patient's with Lesch-Nyhan?
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Deficient in the enzyme hypoxanthine guanine phosphoribosyl transferase
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What does HGPRTase do?
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Metabolizes hypoxanthine and guanine to uric acid
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What disease is HGPRTase deficiency associated with?
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Lesch-Nyhan
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What are the signs/symptoms of Lesch-Nyhan?
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Bizarre impulse for self-mutilation, severe biting of the lips and fingers
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What has already been accomplished in the gene therapy of Lesch-Nyhan
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The wild type gene of the mutated gene has been cloned
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What is still necessary in gene therapy of Lesch-Nyhan?
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An adequate tool to introduce the gene into human cell is needed
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PKU
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Phenylketonuria
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What is the defect in PKU?
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Phenylalanine hydroxylase gene in the liver
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PKU prevalence
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1/12,000 white children
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What does lack of early treatment of children with PKU lead to?
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Severe mental retardation
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What is the only treatment currently available for PKU?
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Phenylalanine-free diet
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What is the goal of gene therapy of PKU?
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To introduce a normal gene to the liver
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What type of genetic defects can be treated?
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Somatic genetic defects
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What type of gene replacement cannot be done?
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Germline
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What does germline gene therapy affect?
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Genetic heritage of the progeny
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What would germline gene therapy change?
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The gene pool of the species
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What type of gene therapy is an ethical issue?
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Germline therapy
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mRNA sequence is what strand of RNA?
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sense strand
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Why is mRNA the sense strand?
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It encodes a gene product
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How are gene products produced from mRNA?
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Unpaired nucleotides are read by tRNA anticodons during ribosomal translation of the message
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What can RNA form when there is an antisense strand of RNA?
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Duplexes
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What is necessary for RNA to form a duplex?
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Complementary RNA strand to the sense strand
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What is the complementary RNA strand to the sense strand?
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Antisense strand
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When an RNA strand forms a duplex what happens?
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Translation is blocked
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Why is translation blocked by mRNA/antisense RNA duplex?
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Ribosome cannot gain access to the mRNA nucleotides and duplex RNA are degraded quickly by cellular RNases
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Anti-sense RNA complementary to proto-oncogene BCL-2 is possible therapy for what?
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B-cell lymphomas and Leukemia's
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Where is BCL-2 located
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Chromosome 18
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What is BCL-2?
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A human proto-oncogene
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What is the product of BCL-2?
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Integral membrane protein located in the membranes of the ER, nuclear envelope and outer membrane of the mitochondria
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The BCL-2 gene is translocated in what?
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B-cell leukemia and B-cell lymphoma
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In B-cell leukemia BCL-2 underwent what?
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Reciprocal translocation with the portion of chromosome 14
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What does the portion of chromosome 14 that undergoes reciprocal translocation with BCL-2 in B-cell leukemia contain?
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Antibody heavy chain
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In t(14;18) translocation places BCL-2 close to what?
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Heavy chain gene enhancer
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In t(14;18) cells what happens to BCL-2 protein expression?
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It is high
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Anti-sense ODNs are what?
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Synthetic polymers
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What are antisense ODNs made up of?
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Deoxynucleotides; monomers; DNA building blocks
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ODN has ______________ deoxynucleotides?
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15-20
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What is the oligo sequence arrangement?
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3' --> 5'
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Oligo sequence is sense or anti-sense?
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anti-sense
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Anti-sense ODNs are therapeutic agents that do what?
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Block particular protein synthesis and inhibit disease process
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ODN binds mRNA to form what?
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Duplex
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What does the ODN/mRNA duplex do?
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Physically blocks ribosome movement along the messenger RNA and increases the rate of mRNA degradation in the cell
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What is required for ODN to be useful in medical treatment?
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Ability to enter target cells, ability to escape DNase digestion and no unpleasant side-effects
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What approach is being used to make sure ODN are able to escape DNase digestion?
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Chemical modification
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What is the main mechanism of ODN uptake?
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Endocytosis
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Is endocytosis efficient uptake of ODN?
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No
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How is uptake of ODN being improved during ODN synthesis?
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Adding large hydrophobic groups to ODN Couple ODN to a ligand that has a receptor on the target cell
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What does adding large hydrophobic groups to ODNs do?
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Increases absorption to cell membrane and endocytosis
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When ODNS are coupled to a ligand that has a receptor on the target cell how is uptake of ODN increased?
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The ODN undergoes endocytosis with the ligand
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Example of ligand that ODN can be coupled with in endocytosis?
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Transferrin
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How can be the phosphate-sugar backbone of anti-sense DNA molecule be modified?
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By replacing one non-bridging or two non-bridging oxygen by phosphodiester monthiophysphate or dithiophosphate respectively
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What diseases are currently being treated or experimentally treated with antisense ODNs?
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HIV, AIDS, CMV, retinitis, Hemorrhagic fever, Ebola, Marburg, Cancer, Familial hypercholesterolemia
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CMV is the abbreviation for what?
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Cytomegalovirus
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What is CMV?
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Frequent opportunistic infectious agent of AIDS patients
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What is FDA approved for use against CMV eye infections and retinitis
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Fomivirsen
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Another name for Fomivirsen?
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Vitravene
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Familial hypercholesterolemia is what?
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high cholesterol with a genetic component
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Imprinted gene expression is determined by what?
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The contributing parent
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In what type of genes are both alleles in a heterozygote not expressed equally?
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Imprinted genes
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When a gene is not considered an imprinted gene describe the expression of alleles
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Both alleles are expressed
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What is an example of a gene that expresses both alleles equally
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Blood
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Where does imprinting start?
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In gametes
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In imprinted genes what happens to one allele?
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It is marked to be inactive in the future embryo
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How is marking of alleles in imprinted genes done?
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By methylation of DNA in the promoters of the gene
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What is methylated in the CG islands of imprinted genes?
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The cytosines
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What does methylation of cytosine prevent?
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Transcription factors from binding promoters
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When transcription factors cannot bind promoters what is inhibited?
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Transcription
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What is the imprinting signal?
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Methylation
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Igf2r gene imprinting in the maternal copy of the gene has an _________________ upstream promoter
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Unmethylated
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The promoter of the Igf2r gene in the maternal copy of the gene is unmethylated and therefore is ______________.
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Active
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Because the promoter of the Igf2r gene in the maternal copy is active it can bind what?
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Transcription factors
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Transcription factors binding to the promoter of the Igf2r gene in the maternal copy allows for what?
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Transcription of the sense strand and production of Igf2r messenger RNA
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The downstream set of CpG islands in the maternal copy of the Igf2r gene is what?
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Methylated
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Which Igf2r gene is imprinted?
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Paternal copy
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The upstream promoter of the paternal copy of the Igf2r is _____________ and therefore ________________.
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Methylated, inactive
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The downstream promoter of the paternal copy of Igf2r is ______________ and therefore ________________.
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Unmethylated, active
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Which promoter binds transcription factors in the paternal copy of the Igf2r gene?
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Downstream
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Because the downstream promoter in the paternal copy of the Igf2r gene binds transcription factors what is transcribed?
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The anti-sense strand
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What is produced by transcription of the paternal copy of the Igf2r gene?
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Antisense RNA that shuts the gene down because it cannot be translated
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In wilms tumors what does the tumor cell inherit?
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Active maternal and paternal copies of the Igf2 gene
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What Igf2 allele is necessary to be normal?
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Paternal
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What is a Wilms tumor?
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Pediatric kidney tumor
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If imprinting in somatic cells fail what is the result?
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Cancer
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What type of disorder is Prader Willie?
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Congenital
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Characteristics of someone with Prader Willie syndrome
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Short stature, mental retardation, polyphagia, obesity, sexual infantilism severe muscular hypotonia, poor responsiveness to external stimuli, strabismus
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Strabismus
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A manifest lack of parallelism of the visual axes of the eyes
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What is the result of strabismus
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Crossed eyes, heterotropia, squint
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What causes Prader Willie syndrome in the majority of cases?
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Small deletion in the paternal derived chromosome 15q11-13
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What causes Prader Willie syndrome in the minority of cases?
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Maternal uniparental disomy in which both chromosome 15's are from the mother
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What type of disorder is Angelman syndrome?
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Congenital disorder
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What is the cause of Angelman syndrome?
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Micro deletion of maternal chromosome 15q-13
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What are the characteristics of Angelman syndrome?
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Mental retardation, ataxia, paroxysms of laughter, seizures, characteristic happy faces, minimal speech
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What type of disorder is Cystic fibrosis?
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Congenital metabolic disorder
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What is the inheritance pattern of Cystic fibrosis?
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Autosomal recessive
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What is the result of cystic fibrosis?
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Abnormal excessive sticky mucus secretions of exocrine glands that cause passageway obstructions
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Meconium ileus
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Poor growth
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What disease is Meconium ileus common in?
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Cystic fibrosis
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Why do patients with cystic fibrosis exhibit poor growth?
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Malabsorption
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What are the characteristics of patients with cystic fibrosis?
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Poor growth, bulky foul stools, emphysema, club fingers, salt depletion
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What is a complication of cystic fibrosis
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Recurrent pneumonia by P. aeruginosa
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Characteristic changes of end stage cystic fibrosis
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Bronchial wall thickening, bronchiectasis, persistent atelectasis
