17. Mutation, Repair, and Recombination

Types of Mutations

17. Mutation, Repair, and Recombination

Types of Mutations

1:39 minutes

Problem 37a

Textbook Question

Infantile cardiomyopathy is a devastating disorder that is fatal during the first year of life due to defects in the function of heart muscles resulting from mitochondrial dysfunction. A study, performed by Götz et al. [(2011). Am. J. Hum. Genet. 88:635–642), identified two different causative mutations in the gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS). One mutation changes a leucine residue at amino acid position 155 to arginine (p.Leu155Arg). The other mutation changes arginine at position 592 to tryptophan (p.Arg592Trp). The mtAlaRS enzyme has an N-terminal domain (amino acids 36–481) that catalyzes tRNA aminoacylation and an internal editing domain (amino acids 484–782) that catalyzes deacylation in the case that the tRNA is charged with the wrong amino acid.
Consider the position of the disease causing missense mutations in the mtAlaRS gene in the context of the known protein domains of this enzyme. What predictions can you make about how these mutations impair protein synthesis within mitochondria in different ways?

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Identify the two mutations described in the problem: p.Leu155Arg and p.Arg592Trp. Note their positions within the mtAlaRS protein and the specific amino acid changes involved.

Determine the location of each mutation relative to the known functional domains of the mtAlaRS enzyme. The N-terminal domain (amino acids 36–481) is responsible for tRNA aminoacylation, while the internal editing domain (amino acids 484–782) is responsible for deacylation.

Analyze the potential impact of the p.Leu155Arg mutation, which occurs within the N-terminal domain. Predict how this mutation might disrupt the aminoacylation process, such as by altering the enzyme's ability to recognize or bind tRNA or the correct amino acid.

Examine the potential impact of the p.Arg592Trp mutation, which occurs within the internal editing domain. Predict how this mutation might impair the enzyme's ability to correct errors in tRNA charging, leading to the incorporation of incorrect amino acids during protein synthesis.

Synthesize the information to predict how these mutations could impair mitochondrial protein synthesis in different ways: one mutation (p.Leu155Arg) may affect the initial charging of tRNA, while the other (p.Arg592Trp) may affect the proofreading and editing process, leading to cumulative errors in mitochondrial protein translation.

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Key Concepts

Here are the essential concepts you must grasp in order to answer the question correctly.

Mitochondrial Function and Protein Synthesis

Mitochondria are the powerhouses of the cell, responsible for energy production and various metabolic processes. They have their own genetic material and machinery for protein synthesis, which is crucial for the function of mitochondrial proteins. Understanding how mitochondrial dysfunction affects protein synthesis is essential, as it can lead to diseases like cardiomyopathy when key enzymes, such as mtAlaRS, are impaired.

Missense Mutations

Missense mutations are a type of point mutation where a single nucleotide change results in the substitution of one amino acid for another in a protein. These mutations can significantly affect protein function, depending on the location and nature of the amino acid change. In the context of mtAlaRS, the specific mutations at positions 155 and 592 may disrupt the enzyme's ability to properly charge tRNA, leading to faulty protein synthesis.

Protein Domains and Functionality

Proteins are often composed of distinct regions known as domains, each responsible for specific functions. In mtAlaRS, the N-terminal domain is involved in tRNA aminoacylation, while the internal editing domain ensures accuracy by removing incorrectly charged amino acids. The location of mutations within these domains can provide insights into how they disrupt the enzyme's overall function, potentially leading to impaired mitochondrial protein synthesis and associated diseases.

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Related Practice

Textbook Question

In an experiment employing the methods of the Ames test, two strains of Salmonella are used. Strain A contains a base-substitution mutation, and Strain B contains a frameshift mutation. Four plates are prepared to test the mutagenicity of the compound ethyl methanesulfonate (EMS). Plate 1 is a control plate with Strain A and S9 extract but no EMS. Plate 2 is also a control plate and contains Strain B and S9 extract but no EMS. Plate 3 contains Strain A along with S9 extract and EMS, and Plate 4 contains Strain B, S9 extract, and EMS.

Characterize the expected distribution of colony growth on the four plates. Defend your growth prediction for each plate.

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Textbook Question

What event is being detected by growth of a colony on any of the four plates?

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Textbook Question

Why is the S9 extract added to each of the plates?

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Textbook Question

Suppose the compound being tested was proflavin instead of EMS. Would this change the Ames test results? Explain why or why not.

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Textbook Question

Infantile cardiomyopathy is a devastating disorder that is fatal during the first year of life due to defects in the function of heart muscles resulting from mitochondrial dysfunction. A study, performed by Götz et al. [(2011). Am. J. Hum. Genet. 88:635–642), identified two different causative mutations in the gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS). One mutation changes a leucine residue at amino acid position 155 to arginine (p.Leu155Arg). The other mutation changes arginine at position 592 to tryptophan (p.Arg592Trp). The mtAlaRS enzyme has an N-terminal domain (amino acids 36–481) that catalyzes tRNA aminoacylation and an internal editing domain (amino acids 484–782) that catalyzes deacylation in the case that the tRNA is charged with the wrong amino acid.

Which mutation would you predict has a more severe impairment of translation in mitochondria, and why?

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Textbook Question

Base-substitution mutations often change the amino acid specified by a codon. For each of the amino acid changes listed, determine which ones can result from a one–base-pair substitution. For those that can result from a one–base-pair substitution, give the possible wild-type and mutant codons, listing multiple possibilities if there is more than one option.

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Textbook Question

The two gels illustrated contain dideoxynucleotide DNA-sequencing information for a wild-type segment and mutant segment of DNA corresponding to the N-terminal end of a protein. The start codon and the next five codons are sequenced.

What is the cause of the mutation?

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Multiple Choice

Which type of mutation is possible due to the redundant nature of the genetic code?

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