Letter

Transcriptional regulator PRDM12 is essential for human pain perception

Received:
Accepted:
Published online:

Abstract

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments1,2. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal3,4. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP)5,6. 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 neurogenesis7,8. 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 therapeutics9,10.

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Change history

  • Corrected online 08 July 2015

    In the version of this article initially published, there was an error with the affiliations for author Roman Chrast. His correct affiliations are: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors are grateful for the participation of the patients and their families in this study. The help of all contributing medical, technical and administrative staff is greatly appreciated. We thank S. Malik for her invaluable work with family A, J.R.P. Madrid and F. Axelrod for advice and discussion and M.F. Passarge for helpful suggestions on the text. D.L.H.B. is a senior Wellcome Clinical Scientist (ref. no. 095698z/11/z). This work was supported by Cambridge NIHR Biomedical Research Centre (Y.-C.C., F.S. and C.G.W.), Austrian Science Fond (P23223-B19 to M.A.-G.), the UK Medical Research Council (M.S.N. and S.S.S.), Association Belge contre les Maladies Neuromusculaires and EU FP7/2007-2013 (grant 2012-305121 (NEUROMICS) to J.B. and P.D.J.), Deutsche Forschungsgemeinschaft (CRC/SFB 1140 to C.B. and KU1587/4-1 to I. Kurth), Gebert-Rüf Stiftung (GRS-046/09 to R.C. and J.S.), and Friedrich-Baur Stiftung (J.S.).

Author information

Author notes

    • Ya-Chun Chen
    •  & Michaela Auer-Grumbach

    These authors contributed equally to this work.

Affiliations

  1. Department of Medical Genetics, University of Cambridge, Cambridge, UK.

    • Ya-Chun Chen
    • , Fay Stafford
    • , Michael S Nahorski
    • , Samiha S Shaikh
    • , Ofélia P Carvalho
    •  & C Geoffrey Woods
  2. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

    • Ya-Chun Chen
    • , Fay Stafford
    • , Michael S Nahorski
    • , Samiha S Shaikh
    • , Ofélia P Carvalho
    • , Adeline K Nicholas
    •  & C Geoffrey Woods
  3. Department of Orthopaedics, Medical University Vienna, Vienna, Austria.

    • Michaela Auer-Grumbach
    • , Maria Schabhüttl
    •  & Reinhard Windhager
  4. Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan.

    • Shinya Matsukawa
    •  & Tatsuo Michiue
  5. Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich, Germany.

    • Manuela Zitzelsberger
    • , Caecilia Weiss
    • , Rolf Stucka
    • , Marina Dusl
    • , Claudia Stendel
    • , Bernd Rautenstrauss
    •  & Jan Senderek
  6. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

    • Andreas C Themistocleous
    • , Annina B Schmid
    •  & David L H Bennett
  7. Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

    • Andreas C Themistocleous
  8. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

    • Tim M Strom
    •  & Thomas Wieland
  9. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Tim M Strom
  10. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

    • Chrysanthi Samara
    •  & Roman Chrast
  11. Disease Mechanism Research Core, RIKEN Brain Science Institute, Saitama, Japan.

    • Adrian W Moore
  12. Neusentis Research Unit, Pfizer, Cambridge, UK.

    • Lily Ting-Yin Cho
    •  & Gareth T Young
  13. School of Health and Rehabilitation Sciences, The University of Queensland, St. Lucia, Australia.

    • Annina B Schmid
  14. Department of Neurology, Istanbul University, Istanbul, Turkey.

    • Yesim Parman
  15. Ambulantes Gesundheitszentrum der Charité Campus Virchow (Humangenetik), Universitätsmedizin Berlin, Berlin, Germany.

    • Luitgard Graul-Neumann
  16. Praxis für Humangenetik Cottbus, Cottbus, Germany.

    • Wolfram Heinritz
  17. Institut für Humangenetik, Universitätsklinikum Leipzig, Leipzig, Germany.

    • Wolfram Heinritz
    •  & Eberhard Passarge
  18. Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.

    • Eberhard Passarge
  19. Department of Dermatology, Our Lady's Children's Hospital, Dublin, Ireland.

    • Rosemarie M Watson
    • , Maeve A McAleer
    •  & Alan D Irvine
  20. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.

    • Jens Michael Hertz
  21. Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.

    • Ute Moog
  22. Neuropädiatrische Ambulanz, Krankenhaus der Barmherzigen Schwestern Linz, Linz, Austria.

    • Manuela Baumgartner
  23. Neurogenetics Unit, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

    • Enza Maria Valente
  24. Departamento de Cirugía Plástica, Hospital Infantil Universitario de San José, Bogotá, Colombia.

    • Diego Pereira
  25. Unidad de Genética, Universidad del Rosario, Bogotá, Colombia.

    • Carlos M Restrepo
  26. Institut für Neuropathologie, Uniklinik RWTH Aachen, Aachen, Germany.

    • Istvan Katona
    •  & Joachim Weis
  27. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

    • Claudia Stendel
  28. Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK.

    • Frank Reimann
  29. SPZ Neuropädiatrie Charité, Universitätsmedizin Berlin, Berlin, Germany.

    • Katja von Au
  30. CharitéCentrum für Zahn-, Mund- und Kieferheilkunde, Arbeitsbereich Kinderzahnmedizin, Universitätsmedizin Berlin, Berlin, Germany.

    • Christian Finke
  31. GENDIA (GENetic DIAgnostic Network), Antwerp, Belgium.

    • Patrick J Willems
  32. Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK.

    • Gulshan Karbani
  33. Department of Neurology, University of California San Francisco, San Francisco, California, USA.

    • Maria Roberta Cilio
  34. Department of Neuroscience, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.

    • Maria Roberta Cilio
  35. Department of Neurology and Neurophysiology, Our Lady's Children's Hospital, Dublin, Ireland.

    • John C McHugh
  36. Department of Neurology, Adelaide & Meath Hospital, Dublin, Ireland.

    • Sinead M Murphy
  37. Academic Unit of Neurology, Trinity College, Dublin, Ireland.

    • Sinead M Murphy
  38. Clinical Medicine, Trinity College, Dublin, Ireland.

    • Alan D Irvine
  39. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.

    • Uffe Birk Jensen
  40. Center for Human Genetics, Bioscientia, Ingelheim, Germany.

    • Carsten Bergmann
  41. Department of Medicine, Renal Division, Freiburg University Medical Center, Freiburg, Germany.

    • Carsten Bergmann
  42. Center for Clinical Research, Freiburg University Medical Center, Freiburg, Germany.

    • Carsten Bergmann
  43. Medizinisch Genetisches Zentrum, Munich, Germany.

    • Bernd Rautenstrauss
  44. Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.

    • Jonathan Baets
    •  & Peter De Jonghe
  45. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

    • Jonathan Baets
    •  & Peter De Jonghe
  46. Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.

    • Jonathan Baets
    •  & Peter De Jonghe
  47. MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, National Hospital for Neurology, London, UK.

    • Mary M Reilly
  48. Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany.

    • Regina Kropatsch
  49. Institute of Human Genetics, Jena University Hospital, Jena, Germany.

    • Ingo Kurth
  50. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

    • Roman Chrast
  51. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

    • Roman Chrast

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Contributions

M.A.-G., Y.P., L.G.-N., W.H., R.M.W., J.M.H., U.M., M.B., D.P., C.M.R., K.v.A., C.F., G.K., M.A.M., J.C.M., S.M.M., A.D.I., U.B.J. and C.G.W. enrolled patients in the study and provided patient care. Y.P., L.G.-N., E.P., J.M.H., E.M.V., P.J.W., M.R.C., C.B., B.R., J.B., P.D.J., M.M.R., R.K., I. Kurth, C.G.W. and J.S. obtained DNA samples, skin biopsies and nerve biopsy specimens. Y.-C.C., M.A.-G., T.M.S., C.W., M.S., T.W., F.S., M.S.N., S.S.S., O.P.C., A.K.N., C.G.W. and J.S. carried out linkage analysis and PRDM12 mutation screening. Y.-C.C., M.Z., C. Samara, A.W.M., R.S. and R.C. performed expression studies on Prdm12. Y.-C.C., S.M., M.Z., C.W., R.S., M.D., C. Stendel, F.R., T.M. and J.S. assessed functional consequences of mutations in PRDM12. A.C.T., A.B.S., I. Katona, J.W. and D.L.H.B. analyzed skin biopsies from CIP patients. S.M. and T.M. performed experiments in Xenopus embryos. Y.-C.C., L.T.-Y.C. and G.T.Y. were responsible for experiments involving pluripotent stem cells. R.S. and J.S. carried out protein modeling. A.W.M., R.W., J.W., I. Kurth and D.L.H.B. gave critical advice. M.A.-G., C.G.W. and J.S. oversaw the project, participated in data analysis and directed and supervised the research. The manuscript was written by Y.-C.C., M.A.-G., C.G.W. and J.S. with input from other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to C Geoffrey Woods or Jan Senderek.

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    Supplementary Text and Figures

    Supplementary Figures 1–10, Supplementary Tables 1–6 and Supplementary Note.