Mutation SHO



Mutations and Muscular Dystrophy To learn why Jake needs to use a wheelchair, watch “Duchenne Muscular Dystrophy” ().1. Duchenne muscular dystrophy is a genetic disease that causes progressive muscle weakness. How could a mutated gene cause muscle weakness? (Hint: Think about what a gene is and how it could affect the muscles.)Each muscle in your legs, arms or back is made up of many muscle fibers (see figure). Each muscle fiber is a muscle cell. Unlike most cells, each muscle fiber has multiple nuclei. The bottom diagram shows how the internal cytoskeleton of a muscle fiber is connected to membrane proteins, which are connected to the extracellular matrix (the layer of proteins that surround a cell). These connections protect the fragile cell membrane against damage caused by the mechanical stresses of repeated muscle contraction and relaxation. Normally, the dystrophin protein is a key player in these connections. However, in Duchenne muscular dystrophy, defective dystrophin doesn’t connect to the membrane proteins. As a result, the mechanical stresses of repeated muscle contractions cause holes in the cell membrane, and the muscle fiber dies. As more and more muscle fibers die, the muscle becomes weaker and weaker.Defective dystrophin also causes death of muscle fibers in the heart, so young men with Duchenne muscular dystrophy typically develop heart failure, which is usually fatal.2. Label the figure to show what goes wrong in the muscles of a boy who has Duchenne muscular dystrophy. Draw arrows from the molecular defect to the effects on muscle cells to the main symptom of Duchenne muscular dystrophy.A mutation is a permanent change in the DNA of a gene. This table shows how a mutated DMD gene can cause Duchenne muscular dystrophy. Gene in DNAProteinCharacteristicsNormal DMD gene provides the instructions to make normal dystrophin protein.Normal dystrophinin muscle cells Normal muscles and normal healthMutated DMD gene provides the instructions to make a non-functional dystrophin protein.No functional dystrophin in muscle cells Muscle cells break down, so boy loses the ability to walk, develops heart problems, and typically dies as a young adult. (Duchenne muscular dystrophy)3. Explain how a mutated DMD gene can result in the inability to walk. Be specific.There are many different mutated versions of the DMD gene. Some of these mutations cause Duchenne muscular dystrophy, but others cause a milder disease called Becker muscular dystrophy.Duchenne muscular dystrophy is more severe. A boy with Duchenne muscular dystrophy typically begins to show muscle weakness by age 5 and needs to use a wheelchair by age 12. He usually dies in his twenties, due to heart failure. His muscle cells do not have any functional dystrophin, so many muscle cells die early in life.Becker muscular dystrophy is milder. Symptoms do not begin until age 12 or later, and a person with Becker muscular dystrophy often survives into his forties. His muscle cells have an abnormal version of dystrophin that is somewhat effective for keeping muscle cells alive.Different mutations of the DMD gene cause Duchenne vs. Becker muscular dystrophy. To understand why, we need to review how genes give the instructions for making proteins.4a. This figure shows how a gene provides the instructions to make a protein. In the boxes, label the process represented by each arrow. Label each type of molecule. 4b. Circle one of the codons in the mRNA.4c. Explain what a codon is. Include the words “nucleotides” and “amino acid” in your answer. Translation makes a protein with the sequence of amino acids that is specified by an mRNA molecule. This codon wheel summarizes which amino acid corresponds to each codon in mRNA. The amino acids are shown in the outer circle. To identify the codons that specify an amino acid, start from the center where the first nucleotide in a codon is shown and move outward to the second and third nucleotides in the codon. 5a. Circle the amino acid Ser (serine; near the top right-hand corner).5b. The codons that code for the amino acid Ser (= serine) are UCU, UCC, ______ and _______.Translation of an mRNA molecule begins at a start codon (AUG). The stop codons indicate where translation ends.The figure below shows how translation occurs inside cells.6a. Translation adds the correct amino acid for each codon in the __________ molecule. 6b. The amino acid that the ribosome has just added to the growing protein molecule is specified by the UUU codon. Write in the abbreviation for this amino acid.6c. Circle a tRNA molecule. 6d. Explain how tRNA molecules and ribosomes work together to add the correct amino acid for each codon in the mRNA molecule.7. The first column of this table shows the beginning of a gene and five different mutations of this part of the gene. Use the base-pairing rules to complete the second column. For each mutation, write in any mRNA codons that will be changed as a result of the mutation and use check marks to indicate codons that will not be changed. Beginning of gene in DNAFirst five mRNA codonsBeginning of ProteinOriginal DNA = TACGCAAGTACCTGA…AUG CGU UCA UGG ACUMet – Arg – Ser – Trp – ThrMutation 1 = TACGCCAGTACCTGA… (nucleotide change underlined)___ ___ ___ ___ ___ ___ ___ ___ ___ ___Mutation 2 = TACGCACGTACCTGA… (nucleotide change underlined)___ ___ ___ ___ ___ ___ ___ ___ ___ ___Mutation 3 = TACGCAAGTACTTGA… (nucleotide change underlined)___ ___ ___ ___ ___ ___ ___ ___ ___ ___Mutation 4 = TACGAAGTACCTGA… (second C deleted)___ ___ ___ ___ ___ ___ ___ ___ ___ ___Mutation 5 = TACGCAAGTACTGA… (third C deleted)___ ___ ___ ___ ___ ___ ___ ___ ___ ___8a. Use the codon wheel to identify any stop codons in the mRNA molecules in the above table. Circle the stop codons.8b. Use the codon wheel to complete the last column of the above table. For each mutation, write in any amino acids that will be changed and use check marks to indicate any amino acids that will not be changed. Use dashes to indicate any amino acids that will be missing as a result of a stop codon. 9a. Explain why one of the above mutations did not result in any change in the amino acid sequence of the protein.9b. A point mutation is a change in a single nucleotide in a gene. Mutations 1-3 are point mutations. Which of these point mutations would have the biggest effect on the protein produced? Explain why. 10. Deletion of a single nucleotide in a gene often results in a very defective protein. Explain why.11a. The majority of muscular dystrophy cases are caused by deletion mutations. These deletion mutations can be grouped into two categories:The number of nucleotides omitted from the mRNA is a multiple of 3.The number of nucleotides omitted from the mRNA is not a multiple of 3.Which type of mutation causes the more severe Duchenne muscular dystrophy? ____Which type of mutation causes the milder Becker muscular dystrophy? _____11b. Explain your reasoning. You may recall that Duchenne muscular dystrophy is very rare in girls, and almost all Duchenne muscular dystrophy patients are boys. The figure below will help you understand why.12a. The DMD gene is located on the X chromosome. A carrier mother has one normal DMD gene and one mutated DMD gene. She does not have muscular dystrophy. Which version of the gene is recessive?___ normal DMD gene___ mutated DMD gene 12b. Explain why Duchenne muscular dystrophy is very rare in girls, and almost all Duchenne muscular dystrophy patients are boys. ................
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