Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood

  • Am J Hum Genet. 2018 Apr 5;102(4):557-573. doi: 10.1016/j.ajhg.2018.02.014.
F-Nora Vögtle  1 ,  Björn Brändl  2 ,  Austin Larson  3 ,  Manuela Pendziwiat  4 ,  Marisa W Friederich  3 ,  Susan M White  5 ,  Alice Basinger  6 ,  Cansu Kücükköse  7 ,  Hiltrud Muhle  4 ,  Johanna A Jähn  4 ,  Oliver Keminer  8 ,  Katherine L Helbig  9 ,  Carolyn F Delto  10 ,  Lisa Myketin  11 ,  Dirk Mossmann  11 ,  Nils Burger  11 ,  Noriko Miyake  12 ,  Audrey Burnett  6 ,  Andreas van Baalen  4 ,  Mark A Lovell  13 ,  Naomichi Matsumoto  12 ,  Maie Walsh  14 ,  Hung-Chun Yu  3 ,  Deepali N Shinde  15 ,  Ulrich Stephani  4 ,  Johan L K Van Hove  3 ,  Franz-Josef Müller  16 ,  Ingo Helbig  17
Affiliations
  • 1. Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg 79104, Germany. Electronic address: [email protected].
  • 2. Department of Psychiatry and Psychotherapy, University Hospital Schleswig Holstein, Kiel 24105, Germany.
  • 3. Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO 80045, USA.
  • 4. Department of Neuropediatrics, Christian-Albrechts-University of Kiel, Kiel 24105, Germany.
  • 5. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
  • 6. Cook Children's Physician Network, Department of Genetics, Fort Worth, TX 76102, USA.
  • 7. Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg 79104, Germany; Faculty of Biology, University of Freiburg, Freiburg 79104, Germany.
  • 8. Fraunhofer-Institut für Molekularbiologie und Angewandte Ökologie IME, ScreeningPort, Hamburg 22525, Germany.
  • 9. Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 10. Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg 97080, Germany.
  • 11. Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg 79104, Germany.
  • 12. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
  • 13. Department of Pathology, University of Colorado, Aurora, CO 80045, USA.
  • 14. Adult Genetic Medicine, Royal Melbourne Hospital, Melbourne, VIC 3052, Australia.
  • 15. Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.
  • 16. Department of Psychiatry and Psychotherapy, University Hospital Schleswig Holstein, Kiel 24105, Germany; Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
  • 17. Department of Neuropediatrics, Christian-Albrechts-University of Kiel, Kiel 24105, Germany; Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: [email protected].
PMID: 29576218 DOI: 10.1016/j.ajhg.2018.02.014
Abstract

Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. Analysis of biopsy Materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent Enzymes. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.

Keywords
mitochondrial disease; mitochondrial presequence protease; mitochondrial protein biogenesis; mitochondrial targeting signal; neurodegeneration.