Transfer RNA and human disease.

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Pathological mutations in tRNA genes and processing enzymes lead to complex clinical phenotypes.
• Mitochondrial tRNA (mt-tRNA) genes are frequent mutation sites, with over 200 linked to diseases affecting protein synthesis and cellular energetics.
• Mutations in tRNA processing enzymes also cause diverse phenotypes by affecting tRNA expression, modification, folding, and maturation.

Purpose of the Study:

• To review recent literature on the link between mitochondrial and cytoplasmic tRNAs, and their processing enzymes, to human diseases.
• To explore the mechanisms underlying the clinical presentation of these diseases, with a focus on neurological disorders.

Main Methods:

• Literature review of recent scientific publications.
• Analysis of mechanisms linking tRNA mutations to disease phenotypes.
• Emphasis on neurological disease manifestations.

Main Results:

• mt-tRNA mutations disrupt aminoacylation, impacting protein synthesis and oxidative phosphorylation, leading to diseases like COX deficiency, mitochondrial myopathy, MERRF, and MELAS.
• mt-tRNA mutations can also cause tissue-specific diseases including hearing loss, retinopathy, diabetes, and cardiomyopathy.
• Mutations in tRNA modifying enzymes affect tRNA function beyond aminoacylation, contributing to disease through altered expression, modification, folding, or maturation.

Conclusions:

• Mutations in tRNAs and their processing enzymes are significant causes of human disease, affecting diverse cellular functions.
• Mitochondrial heteroplasmy influences disease severity and onset.
• Understanding these mechanisms is crucial for diagnosing and potentially treating a wide range of genetic disorders, particularly those affecting the nervous system.