Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease

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 d...

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Main Authors: Lindsey Van Haute, Petra Páleníková, Jia Xin Tang, Pavel A Nash, Mariella T Simon, Angela Pyle, Monika Oláhová, Christopher A Powell, Pedro Rebelo-Guiomar, Alexander Stover, Michael Champion, Charulata Deshpande, Emma L Baple, Karen L Stals, Sian Ellard, Olivia Anselem, Clémence Molac, Giulia Petrilli, Laurence Loeuillet, Sarah Grotto, Tania Attie-Bitach, Jose E Abdenur, Robert W Taylor, Michal Minczuk
Format: Article
Language:English
Published: Springer Nature 2024-11-01
Series:EMBO Molecular Medicine
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Online Access:https://doi.org/10.1038/s44321-024-00172-5
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author Lindsey Van Haute
Petra Páleníková
Jia Xin Tang
Pavel A Nash
Mariella T Simon
Angela Pyle
Monika Oláhová
Christopher A Powell
Pedro Rebelo-Guiomar
Alexander Stover
Michael Champion
Charulata Deshpande
Emma L Baple
Karen L Stals
Sian Ellard
Olivia Anselem
Clémence Molac
Giulia Petrilli
Laurence Loeuillet
Sarah Grotto
Tania Attie-Bitach
Jose E Abdenur
Robert W Taylor
Michal Minczuk
author_facet Lindsey Van Haute
Petra Páleníková
Jia Xin Tang
Pavel A Nash
Mariella T Simon
Angela Pyle
Monika Oláhová
Christopher A Powell
Pedro Rebelo-Guiomar
Alexander Stover
Michael Champion
Charulata Deshpande
Emma L Baple
Karen L Stals
Sian Ellard
Olivia Anselem
Clémence Molac
Giulia Petrilli
Laurence Loeuillet
Sarah Grotto
Tania Attie-Bitach
Jose E Abdenur
Robert W Taylor
Michal Minczuk
author_sort Lindsey Van Haute
collection DOAJ
description 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.
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spelling doaj-art-b5fa508dc9ca49af856798aa0160019c2025-01-19T12:34:35ZengSpringer NatureEMBO Molecular Medicine1757-46842024-11-0117119321010.1038/s44321-024-00172-5Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial diseaseLindsey Van Haute0Petra Páleníková1Jia Xin Tang2Pavel A Nash3Mariella T Simon4Angela Pyle5Monika Oláhová6Christopher A Powell7Pedro Rebelo-Guiomar8Alexander Stover9Michael Champion10Charulata Deshpande11Emma L Baple12Karen L Stals13Sian Ellard14Olivia Anselem15Clémence Molac16Giulia Petrilli17Laurence Loeuillet18Sarah Grotto19Tania Attie-Bitach20Jose E Abdenur21Robert W Taylor22Michal Minczuk23MRC Mitochondrial Biology Unit, University of CambridgeMRC Mitochondrial Biology Unit, University of CambridgeMitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityMRC Mitochondrial Biology Unit, University of CambridgeCHOC Children’s Division of Metabolic DisordersDepartment of Applied Sciences, Faculty of Health & Life Sciences, Northumbria UniversityMitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityMRC Mitochondrial Biology Unit, University of CambridgeMRC Mitochondrial Biology Unit, University of CambridgeCHOC Children’s Division of Metabolic DisordersDepartment of Children’s Inherited Metabolic Diseases, Evelina London Children’s Hospital, Guy’s & St Thomas’ Hospital NHS Foundation TrustManchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation TrustGenomics Laboratory, Royal Devon University Healthcare NHS Foundation TrustGenomics Laboratory, Royal Devon University Healthcare NHS Foundation TrustGenomics Laboratory, Royal Devon University Healthcare NHS Foundation TrustMaternité Port-Royal, Département de Gynécologie-Obstétrique, Hôpital Cochin Broca Hôtel-Dieu, APHPMaternité Port-Royal, Département de Gynécologie-Obstétrique, Hôpital Cochin Broca Hôtel-Dieu, APHPService de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, APHPService de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, APHPUF de Génétique Clinique, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital Trousseau, APHPService de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, APHPCHOC Children’s Division of Metabolic DisordersMitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle UniversityMRC Mitochondrial Biology Unit, University of CambridgeAbstract 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.https://doi.org/10.1038/s44321-024-00172-5Exome SequencingLactic AcidosisMitochondrial DiseaseRNA ProcessingtRNA
spellingShingle Lindsey Van Haute
Petra Páleníková
Jia Xin Tang
Pavel A Nash
Mariella T Simon
Angela Pyle
Monika Oláhová
Christopher A Powell
Pedro Rebelo-Guiomar
Alexander Stover
Michael Champion
Charulata Deshpande
Emma L Baple
Karen L Stals
Sian Ellard
Olivia Anselem
Clémence Molac
Giulia Petrilli
Laurence Loeuillet
Sarah Grotto
Tania Attie-Bitach
Jose E Abdenur
Robert W Taylor
Michal Minczuk
Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease
EMBO Molecular Medicine
Exome Sequencing
Lactic Acidosis
Mitochondrial Disease
RNA Processing
tRNA
title Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease
title_full Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease
title_fullStr Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease
title_full_unstemmed Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease
title_short Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease
title_sort pathogenic pde12 variants impair mitochondrial rna processing causing neonatal mitochondrial disease
topic Exome Sequencing
Lactic Acidosis
Mitochondrial Disease
RNA Processing
tRNA
url https://doi.org/10.1038/s44321-024-00172-5
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