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Structural analysis of mitochondrial rRNA gene variants identified in patients with deafness

Lookup NU author(s): Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Copyright © 2023 Vila-Sanjurjo, Mallo, Elson, Smith, Blakely and Taylor.The last few years have witnessed dramatic advances in our understanding of the structure and function of the mammalian mito-ribosome. At the same time, the first attempts to elucidate the effects of mito-ribosomal fidelity (decoding accuracy) in disease have been made. Hence, the time is right to push an important frontier in our understanding of mitochondrial genetics, that is, the elucidation of the phenotypic effects of mtDNA variants affecting the functioning of the mito-ribosome. Here, we have assessed the structural and functional role of 93 mitochondrial (mt-) rRNA variants thought to be associated with deafness, including those located at non-conserved positions. Our analysis has used the structural description of the human mito-ribosome of the highest quality currently available, together with a new understanding of the phenotypic manifestation of mito-ribosomal-associated variants. Basically, any base change capable of inducing a fidelity phenotype may be considered non-silent. Under this light, out of 92 previously reported mt-rRNA variants thought to be associated with deafness, we found that 49 were potentially non-silent. We also dismissed a large number of reportedly pathogenic mtDNA variants, 41, as polymorphisms. These results drastically update our view on the implication of the primary sequence of mt-rRNA in the etiology of deafness and mitochondrial disease in general. Our data sheds much-needed light on the question of how mt-rRNA variants located at non-conserved positions may lead to mitochondrial disease and, most notably, provide evidence of the effect of haplotype context in the manifestation of some mt-rRNA variants.

Publication metadata

Author(s): Vila-Sanjurjo A, Mallo N, Elson JL, Smith PM, Blakely EL, Taylor RW

Publication type: Article

Publication status: Published

Journal: Frontiers in Physiology

Year: 2023

Volume: 14

Online publication date: 08/06/2023

Acceptance date: 18/04/2023

Date deposited: 10/07/2023

ISSN (electronic): 1664-042X

Publisher: Frontiers Media S.A.


DOI: 10.3389/fphys.2023.1163496


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust
ED431C 2018/57
Mito Foundation
MR/S005021/1Medical Research Council (MRC)
the Lily Foundation
the Pathological Society