Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations
Hochberg, Irit (Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa)
Demain, Leigh A. M. (Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust)
Richer, Julie (Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa)
Thompson, Kyle (Wellcome Centre for Mitochondrial Research, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University)
Urquhart, Jill E. (Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust)
Rea, Alessandro (Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust)
Pagarkar, Waheeda (Royal National ENT and Eastman Dental Hospital, University College London Hospitals)
Rodríguez-Palmero, Agustí (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Schlüter, Agatha (Institut d'Investigació Biomèdica de Bellvitge)
Verdura, Edgard (Institut d'Investigació Biomèdica de Bellvitge)
Pujol, Aurora 1968- (Institut d'Investigació Biomèdica de Bellvitge)
Quijada-Fraile, Pilar (Hospital Universitario 12 de Octubre (Madrid))
Amberger, Albert (Institute of Human Genetics, Medical University Innsbruck)
Deutschmann, Andrea J. (Institute of Human Genetics, Medical University Innsbruck)
Demetz, Sandra (Institute of Human Genetics, Medical University Innsbruck)
Gillespie, Meredith (Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa)
Belyantseva, Inna A. (Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD)
McMillan, Hugh J. (Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa)
Barzik, Melanie (Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD)
Beaman, Glenda M. (Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust)
Motha, Reeya (The Royal London Hospital)
Ng, Kah Ying (Institute of Biotechnology, University of Helsinki)
O'Sullivan, James (Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust)
Williams, Simon G. (Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust)
Bhaskar, Sanjeev S. (Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust)
Lawrence, Isabella R. (Wellcome Centre for Mitochondrial Research, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University)
Jenkinson, Emma M. (Division of Evolution, Infection, and Genomics, School of Biological Sciences, University of Manchester)
Zambonin, Jessica L. (Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa)
Blumenfeld, Zeev (Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa)
Yalonetsky, Sergey (Department of Pediatric Cardiology, Rambam Health Care Campus, Haifa)
Oerum, Stephanie (Newcastle MX Structural Biology Laboratory, Newcastle University)
Rossmanith, Walter (Center for Anatomy and Cell Biology, Medical University of Vienna)
Yue, Wyatt W. (Newcastle MX Structural Biology Laboratory, Newcastle University)
Zschocke, Johannes (Institute of Human Genetics, Medical University Innsbruck)
Munro, Kevin J. (Manchester University NHS Foundation Trust)
Battersby, Brendan J. (Institute of Biotechnology, University of Helsinki)
Friedman, Thomas B. (Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD)
Taylor, Robert W. (Wellcome Centre for Mitochondrial Research, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University)
O'Keefe, Raymond T. (Division of Evolution, Infection, and Genomics, School of Biological Sciences, University of Manchester)
Newman, William G. (Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust)

Fecha:	2021
Resumen:	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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Mitochondria ; Perrault syndrome ; PRORP ; Sensorineural hearing loss ; Primary ovarian insufficiency ; Leukodystrophy ; RNase P ; Rare disease ; MRPP3
Publicado en:	American Journal of Human Genetics, Vol. 108 (november 2021) , p. 2195-2204, ISSN 1537-6605

DOI: 10.1016/j.ajhg.2021.10.002
PMID: 34715011

10 p, 1.3 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Artículos > Artículos de investigación
Artículos > Artículos publicados