Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations

  • Am J Hum Genet. 2021 Nov 4;108(11):2195-2204. doi: 10.1016/j.ajhg.2021.10.002.
Irit Hochberg  1 ,  Leigh A M Demain  2 ,  Julie Richer  3 ,  Kyle Thompson  4 ,  Jill E Urquhart  2 ,  Alessandro Rea  2 ,  Waheeda Pagarkar  5 ,  Agustí Rodríguez-Palmero  6 ,  Agatha Schlüter  7 ,  Edgard Verdura  7 ,  Aurora Pujol  8 ,  Pilar Quijada-Fraile  9 ,  Albert Amberger  10 ,  Andrea J Deutschmann  10 ,  Sandra Demetz  10 ,  Meredith Gillespie  3 ,  Inna A Belyantseva  11 ,  Hugh J McMillan  12 ,  Melanie Barzik  11 ,  Glenda M Beaman  2 ,  Reeya Motha  13 ,  Kah Ying Ng  14 ,  James O'Sullivan  2 ,  Simon G Williams  2 ,  Sanjeev S Bhaskar  2 ,  Isabella R Lawrence  4 ,  Emma M Jenkinson  15 ,  Jessica L Zambonin  3 ,  Zeev Blumenfeld  16 ,  Sergey Yalonetsky  17 ,  Stephanie Oerum  18 ,  Walter Rossmanith  19 ,  Genomics England Research Consortium ,  Wyatt W Yue  18 ,  Johannes Zschocke  10 ,  Kevin J Munro  20 ,  Brendan J Battersby  14 ,  Thomas B Friedman  11 ,  Robert W Taylor  4 ,  Raymond T O'Keefe  21 ,  William G Newman  22
Affiliations
  • 1. Institute of Endocrinology, Diabetes, and Metabolism, Rambam Health Care Campus, Haifa 3109601, Israel; Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3109601, Israel.
  • 2. Division of Evolution, Infection, and Genomics, School of Biological Sciences, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK.
  • 3. Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
  • 4. Wellcome Centre for Mitochondrial Research, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
  • 5. Royal National ENT and Eastman Dental Hospital, University College London Hospitals, London WC1E 6DG, UK.
  • 6. Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, and Center for Biomedical Research on Rare Diseases, 08908 Barcelona, Spain; Paediatric Neurology Unit, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Barcelona, Spain.
  • 7. Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, and Center for Biomedical Research on Rare Diseases, 08908 Barcelona, Spain.
  • 8. Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, and Center for Biomedical Research on Rare Diseases, 08908 Barcelona, Spain; Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Spain.
  • 9. Unit of Mitochondrial and Inherited Metabolic Diseases, Pediatric Department, University Hospital 12 de Octubre, National Reference Center, European Reference Network for Hereditary Metabolic Disorders, 28041 Madrid, Spain.
  • 10. Institute of Human Genetics, Medical University Innsbruck, Innsbruck 6020, Austria.
  • 11. Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892-3729, USA.
  • 12. Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
  • 13. The Royal London Hospital, Whitechapel Road, Whitechapel, London E1 1FR, UK.
  • 14. Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland.
  • 15. Division of Evolution, Infection, and Genomics, School of Biological Sciences, University of Manchester, Manchester M13 9PL, UK.
  • 16. Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3109601, Israel.
  • 17. Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON K1H 8L1, Canada; Department of Pediatric Cardiology, Rambam Health Care Campus, Haifa 3109601, Israel.
  • 18. Newcastle MX Structural Biology Laboratory, Newcastle University, Medical School, NUBI Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
  • 19. Center for Anatomy and Cell Biology, Medical University of Vienna, 1090 Vienna, Austria.
  • 20. Manchester Centre for Audiology and Deafness, School of Health Sciences, University of Manchester, Manchester M13 9PL, UK; Manchester University NHS Foundation Trust, Manchester M13 9WL, UK.
  • 21. Division of Evolution, Infection, and Genomics, School of Biological Sciences, University of Manchester, Manchester M13 9PL, UK. Electronic address: [email protected].
  • 22. Division of Evolution, Infection, and Genomics, School of Biological Sciences, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK. Electronic address: [email protected].
PMID: 34715011 DOI: 10.1016/j.ajhg.2021.10.002
Abstract

Human mitochondrial RNase P (mt-RNase P) is responsible for 5' end processing of mitochondrial precursor tRNAs, a vital step in mitochondrial RNA maturation, and is comprised of three protein subunits: TRMT10C, SDR5C1 (HSD10), and PRORP. Pathogenic variants in TRMT10C and SDR5C1 are associated with distinct recessive or x-linked infantile onset disorders, resulting from defects in mitochondrial RNA processing. We report four unrelated families with multisystem disease associated with bi-allelic variants in PRORP, the metallonuclease subunit of mt-RNase P. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. Fibroblasts from affected individuals in two families demonstrated decreased steady state levels of PRORP, an accumulation of unprocessed mitochondrial transcripts, and decreased steady state levels of mitochondrial-encoded proteins, which were rescued by introduction of the wild-type PRORP cDNA. In mt-tRNA processing assays performed with Recombinant mt-RNase P proteins, the disease-associated variants resulted in diminished mitochondrial tRNA processing. Identification of disease-causing variants in PRORP indicates that pathogenic variants in all three subunits of mt-RNase P can cause mitochondrial dysfunction, each with distinct pleiotropic clinical presentations.

Keywords
MRPP3; PRORP; Perrault syndrome; RNase P; leukodystrophy; mitochondria; primary ovarian insufficiency; rare disease; sensorineural hearing loss.