Abstract
Mutations of mitochondrial DNA are linked to many human diseases. Despite the identification of a large number of variants in the mitochondrially encoded rRNA (mt-rRNA) genes, the evidence supporting their pathogenicity is, at best, circumstantial. Establishing the pathogenicity of these variations is of major diagnostic importance. Here, we aim to estimate the disruptive effect of mt-rRNA variations on the function of the mitochondrial ribosome. In the absence of direct biochemical methods to study the effect of mt-rRNA variations, we relied on the universal conservation of the rRNA fold to infer their disruptive potential. Our method, named heterologous inferential analysis or HIA, combines conservational information with functional and structural data obtained from heterologous ribosomal sources. Thus, HIA's predictive power is superior to the traditional reliance on simple conservation indexes. By using HIA, we have been able to evaluate the disruptive potential for a subset of uncharacterized 12S mt-rRNA variations. Our analysis revealed the existence of variations in the rRNA component of the human mitoribosome with different degrees of disruptive power. In cases where sufficient information regarding the genetic and pathological manifestation of the mitochondrial phenotype is available, HIA data can be used to predict the pathogenicity of mt-rRNA mutations. In other cases, HIA analysis will allow the prioritization of variants for additional investigation. Eventually, HIA-inspired analysis of potentially pathogenic mt-rRNA variations, in the context of a scoring system specifically designed for these variants, could lead to a powerful diagnostic tool.
Highlights
More than 550 mitochondrial DNA mutations and sequence variants have been associated with human disease [1]
Evaluation of evidence used to identify mitochondrial DNA (mtDNA) mutations in other mtDNA genes indicates that the absence of the variant in controls is important evidence of pathogenicity
While our results show that Conservation index (Ci) have some potential to predict the assignment of an important subset of mutations according to their heterologous inferential analysis (HIA)-predicted disruptive power, especially those within the ‘expectedly’ category, Cis cannot be relied upon for the assignment of pathogenicity to most mutations
Summary
More than 550 mitochondrial DNA (mtDNA) mutations and sequence variants have been associated with human disease [1]. The assignment of pathogenicity to mtDNA mutations is a difficult task. This is in no small part due to high levels of mtDNA variation in human populations and the extremely heterogeneous clinical presentations of many known mtDNA mutations. Due to these and other difficulties, the evidence for pathogenicity has been rather weak in some cases, especially in the context of rRNA variation. Some authors have suggested that a number of these associations might be erroneous [3,4,5,6,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
