Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease

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.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2024-11-20
DOI
https://doi.org/10.1038/s44321-024-00172-5
Citations
4
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
0.94

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article

Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease

Tania Attié‐Bitach, Pedro Rebelo‐Guiomar, Karen Stals, Clémence Molac et al.
4 citations
EMBO Molecular Medicine
Mitochondrial Function and Pathology
0.94
article

Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease

Tania Attié‐Bitach, Pedro Rebelo‐Guiomar, Karen Stals, Clémence Molac, P. Nash, Giulia Petrilli, Jia Xin Tang, Christopher A. Powell, Michal A. Minczuk, Sarah Grotto, Petra Páleníková, Monika Oláhová, Alexander E. Stover, Olivia Anselem, Laurence Lœuillet, José E. Abdenur, Mariella Simon, Sian Ellard, Michael Champion, Emma L. Baple, Lindsey Van Haute, Robert William Taylor, Angela Pyle, Charulata Deshpande
article en
4 citations

Abstract

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.

EMBO Molecular MedicineVol. 17(1)
Broad Institute (US), Hôpital Necker-Enfants Malades (FR), Children's Hospital of Orange County (US), Inserm (FR), Guy's and St Thomas' NHS Foundation Trust (GB), University of California, Irvine (US), Université Paris Cité (FR), University of Exeter (GB), University of Cambridge (GB), Royal Devon & Exeter NHS Foundation Trust (GB), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), University of Manchester (GB), Northumbria University (GB), Sorbonne Université (FR), Hôpital Armand-Trousseau (FR), Bridge University (SS), Assistance Publique – Hôpitaux de Paris (FR), Maternité Port Royal (FR), Wellcome Centre for Mitochondrial Research (GB), Evelina London Children's Healthcare (GB), Institut des Maladies Génétiques Imagine (FR), Max Planck Institute for Multidisciplinary Sciences (DE), MRC Mitochondrial Biology Unit (GB), Newcastle University (GB)
LifeArc, French Muscular Dystrophy Association, Champ Foundation, Pathological Society of Great Britain and Ireland, Newcastle University, Mito Foundation, Lily Foundation, Medical Research Council, Faculty of Medical Sciences, Newcastle University, Wellcome Trust Centre for Mitochondrial Research, HORIZON EUROPE Marie Sklodowska-Curie Actions
Good health and well-being
Openalex Percentile: Top 25%
Mitochondrial Function and Pathology
0.94
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