Transcriptional regulator PRDM12 is essential for human pain perception

  • Nat Genet. 2015 Jul;47(7):803-8. doi: 10.1038/ng.3308.
Ya-Chun Chen  1 ,  Michaela Auer-Grumbach  2 ,  Shinya Matsukawa  3 ,  Manuela Zitzelsberger  4 ,  Andreas C Themistocleous  5 ,  Tim M Strom  6 ,  Chrysanthi Samara  7 ,  Adrian W Moore  8 ,  Lily Ting-Yin Cho  9 ,  Gareth T Young  9 ,  Caecilia Weiss  4 ,  Maria Schabhüttl  2 ,  Rolf Stucka  4 ,  Annina B Schmid  10 ,  Yesim Parman  11 ,  Luitgard Graul-Neumann  12 ,  Wolfram Heinritz  13 ,  Eberhard Passarge  14 ,  Rosemarie M Watson  15 ,  Jens Michael Hertz  16 ,  Ute Moog  17 ,  Manuela Baumgartner  18 ,  Enza Maria Valente  19 ,  Diego Pereira  20 ,  Carlos M Restrepo  21 ,  Istvan Katona  22 ,  Marina Dusl  4 ,  Claudia Stendel  23 ,  Thomas Wieland  24 ,  Fay Stafford  1 ,  Frank Reimann  25 ,  Katja von Au  26 ,  Christian Finke  27 ,  Patrick J Willems  28 ,  Michael S Nahorski  1 ,  Samiha S Shaikh  1 ,  Ofélia P Carvalho  1 ,  Adeline K Nicholas  29 ,  Gulshan Karbani  30 ,  Maeve A McAleer  15 ,  Maria Roberta Cilio  31 ,  John C McHugh  32 ,  Sinead M Murphy  33 ,  Alan D Irvine  34 ,  Uffe Birk Jensen  35 ,  Reinhard Windhager  2 ,  Joachim Weis  22 ,  Carsten Bergmann  36 ,  Bernd Rautenstrauss  37 ,  Jonathan Baets  38 ,  Peter De Jonghe  38 ,  Mary M Reilly  39 ,  Regina Kropatsch  40 ,  Ingo Kurth  41 ,  Roman Chrast  42 ,  Tatsuo Michiue  3 ,  David L H Bennett  43 ,  C Geoffrey Woods  1 ,  Jan Senderek  4
Affiliations
  • 1. 1] Department of Medical Genetics, University of Cambridge, Cambridge, UK. [2] Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
  • 2. Department of Orthopaedics, Medical University Vienna, Vienna, Austria.
  • 3. Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan.
  • 4. Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich, Germany.
  • 5. 1] Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. [2] Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
  • 6. 1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [2] Institute of Human Genetics, Technische Universität München, Munich, Germany.
  • 7. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
  • 8. Disease Mechanism Research Core, RIKEN Brain Science Institute, Saitama, Japan.
  • 9. Neusentis Research Unit, Pfizer, Cambridge, UK.
  • 10. 1] Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. [2] School of Health and Rehabilitation Sciences, The University of Queensland, St. Lucia, Australia.
  • 11. Department of Neurology, Istanbul University, Istanbul, Turkey.
  • 12. Ambulantes Gesundheitszentrum der Charité Campus Virchow (Humangenetik), Universitätsmedizin Berlin, Berlin, Germany.
  • 13. 1] Praxis für Humangenetik Cottbus, Cottbus, Germany. [2] Institut für Humangenetik, Universitätsklinikum Leipzig, Leipzig, Germany.
  • 14. 1] Institut für Humangenetik, Universitätsklinikum Leipzig, Leipzig, Germany. [2] Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
  • 15. Department of Dermatology, Our Lady's Children's Hospital, Dublin, Ireland.
  • 16. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
  • 17. Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
  • 18. Neuropädiatrische Ambulanz, Krankenhaus der Barmherzigen Schwestern Linz, Linz, Austria.
  • 19. Neurogenetics Unit, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
  • 20. Departamento de Cirugía Plástica, Hospital Infantil Universitario de San José, Bogotá, Colombia.
  • 21. Unidad de Genética, Universidad del Rosario, Bogotá, Colombia.
  • 22. Institut für Neuropathologie, Uniklinik RWTH Aachen, Aachen, Germany.
  • 23. 1] Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich, Germany. [2] German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  • 24. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
  • 25. Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK.
  • 26. SPZ Neuropädiatrie Charité, Universitätsmedizin Berlin, Berlin, Germany.
  • 27. CharitéCentrum für Zahn-, Mund- und Kieferheilkunde, Arbeitsbereich Kinderzahnmedizin, Universitätsmedizin Berlin, Berlin, Germany.
  • 28. GENDIA (GENetic DIAgnostic Network), Antwerp, Belgium.
  • 29. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
  • 30. Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK.
  • 31. 1] Department of Neurology, University of California San Francisco, San Francisco, California, USA. [2] Department of Neuroscience, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
  • 32. Department of Neurology and Neurophysiology, Our Lady's Children's Hospital, Dublin, Ireland.
  • 33. 1] Department of Neurology, Adelaide &Meath Hospital, Dublin, Ireland. [2] Academic Unit of Neurology, Trinity College, Dublin, Ireland.
  • 34. 1] Department of Dermatology, Our Lady's Children's Hospital, Dublin, Ireland. [2] Clinical Medicine, Trinity College, Dublin, Ireland.
  • 35. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
  • 36. 1] Center for Human Genetics, Bioscientia, Ingelheim, Germany. [2] Department of Medicine, Renal Division, Freiburg University Medical Center, Freiburg, Germany. [3] Center for Clinical Research, Freiburg University Medical Center, Freiburg, Germany.
  • 37. 1] Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich, Germany. [2] Medizinisch Genetisches Zentrum, Munich, Germany.
  • 38. 1] Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. [3] Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
  • 39. MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, National Hospital for Neurology, London, UK.
  • 40. Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany.
  • 41. Institute of Human Genetics, Jena University Hospital, Jena, Germany.
  • 42. 1] Institute of Human Genetics, Technische Universität München, Munich, Germany. [2] Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. [3] Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
  • 43. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
PMID: 26005867 DOI: 10.1038/ng.3308
Abstract

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.