Chrzanowska-Lightowlers ZMA

Elson JL

Greaves LC

Lightowlers RN

Rodenburg RJT

Smith PM

Taylor RW

Vila-Sanjurjo A

Wortmann SB

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\u27s 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 prioritisation 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

Newcastle University E-Prints

English

The role of the mitochondrial ribosome in human disease: Searching for mutations in 12S mitochondrial rRNA with high disruptive potential

https://eprint.ncl.ac.uk/fulltext.aspx?url=195418/6C6F7A7B-DD36-4CE5-BC29-F40316746D28.pdf&pub_id=195418

The role of the mitochondrial ribosome in human disease: Searching for mutations in 12S mitochondrial rRNA with high disruptive potential

Abstract

Similar works

Full text

Available Versions

Newcastle University E-Prints