Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease

EMBO Mol Med. 2025 Jan;17(1):193-210. doi: 10.1038/s44321-024-00172-5.

Lindsey Van Haute ¹, Petra Páleníková ¹ ², Jia Xin Tang ³ ⁴, Pavel A Nash ¹, Mariella T Simon ⁵, Angela Pyle ⁶, Monika Oláhová ³ ⁶, Christopher A Powell ¹, Pedro Rebelo-Guiomar ¹ ⁷, Alexander Stover ⁵, Michael Champion ⁸, Charulata Deshpande ⁹ ¹⁰, Emma L Baple ¹¹ ¹² ¹³, Karen L Stals ¹¹, Sian Ellard ¹¹ ¹², Olivia Anselem ¹⁴, Clémence Molac ¹⁴, Giulia Petrilli ¹⁵, Laurence Loeuillet ¹⁵, Sarah Grotto ¹⁶, Tania Attie-Bitach ¹⁵ ¹⁷, Jose E Abdenur ⁵ ¹⁸, Robert W Taylor ¹⁹ ²⁰, Michal Minczuk ²¹ ²²

Affiliations

1 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
2 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3 Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
4 Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
5 CHOC Children's Division of Metabolic Disorders, Orange, CA, USA.
6 Department of Applied Sciences, Faculty of Health & Life Sciences, Northumbria University, Newcastle upon Tyne, UK.
7 Department of Biochemistry, University of Cambridge, Tennis Court Road, CB1 2GA, Cambridge, UK.
8 Department of Children's Inherited Metabolic Diseases, Evelina London Children's Hospital, Guy's & St Thomas' Hospital NHS Foundation Trust, London, UK.
9 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
10 Department of Clinical Genetics, Guy's Hospital, Guy's & St Thomas' Hospital NHS Foundation Trust, London, UK.
11 Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
12 Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK.
13 Peninsula Clinical Genetics Service, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
14 Maternité Port-Royal, Département de Gynécologie-Obstétrique, Hôpital Cochin Broca Hôtel-Dieu, APHP, Paris, France.
15 Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, APHP, Paris, France.
16 UF de Génétique Clinique, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital Trousseau, APHP, Paris, France.
17 INSERM UMR 1163, Imagine Institute, Genetics and Development of the Cerebral Cortex, Université Paris Cité, Paris, France.
18 University of California, Irvine, Department of Pediatrics, Irvine, CA, USA.
19 Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. [email protected].
20 NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. [email protected].
21 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK. [email protected].
22 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. [email protected].

PMID: 39567835 DOI: 10.1038/s44321-024-00172-5

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.

Keywords

Exome Sequencing; Lactic Acidosis; Mitochondrial Disease; RNA Processing; tRNA.

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