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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2024-11-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-024-00172-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594504385822720 |
|---|---|
| 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. |
| format | Article |
| id | doaj-art-b5fa508dc9ca49af856798aa0160019c |
| institution | Kabale University |
| issn | 1757-4684 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| 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 |
| work_keys_str_mv | AT lindseyvanhaute pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT petrapalenikova pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT jiaxintang pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT pavelanash pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT mariellatsimon pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT angelapyle pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT monikaolahova pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT christopherapowell pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT pedrorebeloguiomar pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT alexanderstover pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT michaelchampion pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT charulatadeshpande pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT emmalbaple pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT karenlstals pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT sianellard pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT oliviaanselem pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT clemencemolac pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT giuliapetrilli pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT laurenceloeuillet pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT sarahgrotto pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT taniaattiebitach pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT joseeabdenur pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT robertwtaylor pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease AT michalminczuk pathogenicpde12variantsimpairmitochondrialrnaprocessingcausingneonatalmitochondrialdisease |