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?

Verified step by step guidance

1. Identify the location of each mutation within the mtAlaRS protein domains: p.Leu155Arg is within the N-terminal domain (amino acids 36–481), and p.Arg592Trp is within the internal editing domain (amino acids 484–782).
2. Understand the function of the N-terminal domain: It catalyzes tRNA aminoacylation, which is the process of attaching an amino acid to its corresponding tRNA.
3. Predict the impact of the p.Leu155Arg mutation: Since this mutation is in the N-terminal domain, it may impair the enzyme's ability to correctly attach alanine to its tRNA, leading to defective protein synthesis.
4. Understand the function of the internal editing domain: It catalyzes deacylation, which corrects errors by removing incorrectly attached amino acids from tRNA.
5. Predict the impact of the p.Arg592Trp mutation: This mutation in the editing domain may reduce the enzyme's ability to correct errors, allowing mischarged tRNAs to participate in protein synthesis, potentially leading to dysfunctional proteins.

Key Concepts

Mitochondrial Function and Protein Synthesis

Mitochondria are essential organelles responsible for energy production and play a critical role in protein synthesis. They contain their own DNA and machinery for translating mitochondrial genes into proteins. Understanding how mitochondrial dysfunction affects protein synthesis is crucial, as it can lead to various disorders, including cardiomyopathy, due to impaired energy metabolism and protein production.

Missense Mutations

Missense mutations are a type of genetic alteration where a single nucleotide change results in the substitution of one amino acid for another in a protein. This can affect the protein's structure and function, potentially leading to diseases. In the context of mtAlaRS, the specific amino acid changes (p.Leu155Arg and p.Arg592Trp) can disrupt the enzyme's ability to properly charge tRNA, impacting mitochondrial protein synthesis.

Protein Domains and Functionality

Proteins are often composed of distinct regions called 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. Mutations located in or near these domains can lead to functional impairments, affecting the enzyme's ability to synthesize proteins accurately within mitochondria.