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Lookup NU author(s): Yasmin Tang, Dr Angela Pyle, Dr Monika Olahova, Professor Robert Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Here, we report that disease-causing PDE12 variants in three unrelated families are associated with mitochondrial respiratory chain deficiencies and wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. Whole exome sequencing of affected probands revealed novel, segregating bi-allelic missense PDE12 variants affecting conserved residues. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing (MPAT-Seq) revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein. Our data suggest that PDE12 regulates mitochondrial RNA processing and its loss results in neurological and muscular phenotypes.
Author(s): Van Haute L, Palenikova P, Tang JX, Nash PA, Simon MT, Pyle A, Olahova M, Powell CA, Rebelo-Guiomar P, Stover A, Champion M, Deshpande C, Baple EL, Stals KL, Ellard S, Anselem O, Molac C, Petrilli G, Loeuillet L, Grotto S, Attie-Bitach T, Abdenur JE, Taylor RW, Minczuk M
Publication type: Article
Publication status: Published
Journal: EMBO Molecular Medicine
Year: 2024
Pages: epub ahead of print
Online publication date: 20/11/2024
Acceptance date: 29/10/2024
Date deposited: 05/12/2024
ISSN (print): 1757-4676
ISSN (electronic): 1757-4684
Publisher: Springer Nature
URL: https://doi.org/10.1038/s44321-024-00172-5
DOI: 10.1038/s44321-024-00172-5
Data Access Statement: Microarray data has been deposited in ArrayExpress (accession number E-MTAB-14251). Diagnostic genomic data were available from the authors on request, as due to consent agreement restrictions, patient diagnostic genomic data could not be made freely available and were therefore not deposited in a public database. The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-024-00172-5.
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