Molecular Biology In Medicine. Chapter 4. Inherited Diseases. Mutations. Gene mutations can be either inherited from a parent or acquired. A hereditary mutation is a mistake that is present in the DNA of virtually all body cells. - PowerPoint PPT Presentation
Molecular Biology In MedicineChapter 4Inherited DiseasesMutationsGene mutations can be either inherited from a parent or acquired. A hereditary mutation is a mistake that is present in the DNA of virtually all body cells. Hereditary mutations are also called germ line mutations because the gene change exists in the reproductive cells (eggs and sperm) and can be passed from generation to generation, from parent to newborn.The mutation is copied every time body cells divide.Mutations occur all the time in every cell in the body. Each cell, however, has the remarkable ability to recognize mistakes and fix them before it passes them along to its descendants. But a cell's DNA repair mechanisms can fail, or be overwhelmed, or become less efficient with age. Over time, mistakes can accumulate.
Downs SyndromeCaused by non-disjunction of the 21st chromosome.This means that the individual has a trisomy (i.e. 3 copies) chromosome 21.
Down Syndromeor Trisomy 21
Symptoms of Down SyndromeUpward slant to eyes.Small ears that fold over at the top.Small, flattened nose.Small mouth, making tongue appear large.Short neck.Small hands with short fingers.Low muscle tone.Symptoms of Down SyndromeSingle deep crease across center of palm.Looseness of joints.Small skin folds at the inner corners of the eyes.Excessive space between first and second toe.In addition, down syndrome always involves some degree of mental retardation, from mild to severe. In most cases, the mental retardation is mild to moderate.
Sickle Cell Anemia
An inherited, chronic disease in which the red blood cells, normally disc-shaped, become crescent shaped. As a result, they function abnormally and cause small blood clots. These clots give rise to recurrent painful episodes called "sickle cell pain crises".
Cystic Fibrosis (CF)MonogenicCause: deletion of only 3 bases of a gene on chromosome 7Fluid in lungs, potential respiratory failureCommon among Caucasians1 in 20 are carriersTherefore is it dominant or recessive?Tay-Sachs diseaseMonogenic, autosomal recessiveCentral nervous system degrades, ultimately causing death.Most common among people of Jewish eastern Europe descent and French Canadians.May provide resistance to CholeraMuscular DystrophyWhat Is Muscular Dystrophy?Muscular dystrophy is a disease in which the muscles of the body get weaker and weaker and slowly stop working because of a lack of a certain protein (see the relationship to genetics?)Can be passed on by one or both parents, depending on the form of MD (therefore is autosomal dominant and recessive)Hemophilia, the royal diseaseHaemophilia is the oldest known hereditary bleeding disorder.Caused by a single mutation to a gene on the X chromosome.There are about 20,000 haemophilia patients in the United States.One can bleed to death with small cuts or bruises .
The severity of haemophilia is related to the amount of the clotting factor in the blood. About 70% of hemophilia patients have less than one percent of the normal amount and, thus, have severe haemophilia.
X-linked Inheritance pedigree chartHuntingtons Disease
Huntington's disease (HD) is an inherited, degenerative brain disorder which results in an eventual loss of both mental and physical control. The disease is also known as Huntington's chorea. Chorea means "dance-like movements" and refers to the uncontrolled motions often associated with the disease.
Scientists have discovered that the abnormal protein produced by the Huntington's disease gene, which contains an elongated stretch of amino acids called glutamines, binds more tightly to HAP-1 than the normal protein does. Phenylketonuria or PKUPeople with PKU cannot consume any product that contains aspartame.PKU is a metabolic disorder that results when the PKU gene is inherited from both parents (recessive or dominant? Monogenic or chromosomal?) Caused by a deficiency of an enzyme which is necessary for proper metabolism of an amino acid called phenylalanine. PKUPhenylalanine is an essential amino acid and is found in nearly all foods which contain protein, dairy products, nuts, beans, tofu, etc.A low protein diet must be followed. Brain damage can result if the diet is not followed causing mental retardation and mousy body odor (phenylacetic acid is in sweat).
Cause: x-linked recessive8% males and 0.64% females affected. Why the difference?Individuals are unable to distinguish shades of red-green.Are you color blind?
GenesAre carried on a chromosomeThe basic unit of heredityEncode how to make a proteinDNARNA proteinsProteins carry out most of lifes function.When altered causes dysfunction of a proteinWhen there is a mutation in the gene, then it will change the codon, which will change which amino acid is called for which will change the conformation of the protein which will change the function of the protein. Genetic disorders result from mutations in the genome.
26Picture of a Chromosome
27What is Gene TherapyIt is a technique for correcting defective genes that are responsible for disease developmentThere are four approaches:A normal gene inserted to compensate for a nonfunctional gene.An abnormal gene traded for a normal geneAn abnormal gene repaired through selective reverse mutationChange the regulation of gene pairs28Is the most common approachThe abnormal gene would be swapped by homologous recombinationWould cause a return to normal functionControl expression of genes. Similar to epistasis, when one gene affects the expression of another gene. The BeginningIn the 1980s, Scientists began to look into gene therapy.They would insert human genes into a bacteria cell.Then the bacteria cell would transcribe and translate the information into a proteinThen they would introduce the protein into human cells29The First CaseThe first gene therapy was performed on September 14th, 1990Ashanti DeSilva was treated for SCIDSever combined immunodeficiency Doctors removed her white blood cells, inserted the missing gene into the WBC, and then put them back into her blood stream.This strengthened her immune systemOnly worked for a few months 30How It WorksA vector delivers the therapeutic gene into a patients target cellThe target cells become infected with the viral vectorThe vectors genetic material is inserted into the target cellFunctional proteins are created from the therapeutic gene causing the cell to return to a normal state31A vector is a carrier molecule, usually a virusThe target cells are usually in the liver or lung
32VirusesReplicate by inserting their DNA into a host cellGene therapy can use this to insert genes that encode for a desired protein to create the desired traitFour different types33RetrovirusesCreated double stranded DNA copies from RNA genomeThe retrovirus goes through reverse transcription using reverse transcriptase and RNAthe double stranded viral genome integrates into the human genome using integraseintegrase inserts the gene anywhere because it has no specific siteMay cause insertional mutagenesisOne gene disrupts another genes code (disrupted cell division causes cancer from uncontrolled cell division)vectors used are derived from the human immunodeficiency virus (HIV) and are being evaluated for safety34AdenovirusesAre double stranded DNA genome that cause respiratory, intestinal, and eye infections in humansThe inserted DNA is not incorporate into genome Not replicated thoughHas to be reinserted when more cells divideE.g.: Common cold 35Adenovirus cont.
36Adeno-associated VirusesAdeno-associated Virus- small, single stranded DNA that insert genetic material at a specific point on chromosome 19From parvovirus family- causes no known disease and doesn't trigger patient immune response. Low information capacitygene is always "on" so the protein is always being expressed, possibly even in instances when it isn't needed.hemophilia treatments, for example, a gene-carrying vector could be injected into a muscle, prompting the muscle cells to produce Factor IX and thus prevent bleeding.Study by Wilson and Kathy High (University of Pennsylvania), patients have not needed Factor IX injections for more than a year37