Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti (original) (raw)

Nature volume 405, pages 466–472 (2000)Cite this article

Abstract

Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring1. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation2. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-κB essential modulator)/IKKγ (IκB kinase-γ) has been mapped to a position 200 kilobases proximal to the factor VIII locus4. NEMO is required for the activation of the transcription factor NF-κB and is therefore central to many immune, inflammatory and apoptotic pathways5,6,7,8,9. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-κB activation is defective in IP cells.

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Acknowledgements

The IP Consortium thanks S. Emmerich, Director of the National Incontinentia Pigmenti Foundation, for financial and practical support, and for fostering a collaborative spirit throughout. We also thank the participating families for their cooperation, and their attending physicians for sharing information and facilitating enrolments: in particular V. Murday, S. Landy, J. Dean, M. C. Hors-Cayla, N. Dahl and M. Gonzales. This work has been supported by Action Research UK (S.J.K.).; Association Francaise contre les Myodystrophie (A.M.); The Foundation Fighting Blindness; Research to Prevent Blindness, Inc.; (R.A.L.); the NIH (DLN); Telethon, Italy (M.D'U); Deutsche Forschungsgemeinschaft; the European Community (EC) Fifth Framework Programme (A.P.); Association pour la Recherche sur le Cancer, Ligue Nationale contre le Cancer and EC (A.I.) and by the National Incontinentia Pigmenti Foundation. R.A.L. is a Research to Prevent Blindness Senior Scientific Investigator. A.I. and G.C. thank C. Bessia for technical help.

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Author notes

  1. Asmae Smahi, Nina S. Heiss, Teresa Esposito, Hayley Woffendin, Swaroop Aradhya and M. Levy: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Genetics, Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERMU-393 Hopital Necker-Enfants Malades, Paris, 75015, France
    Asmae Smahi, P. Vabres, S. Heuertz & A. Munnich
  2. Unité de Biologie Moléculaire de l'Expression Génique URA 1773 CNRS, Institut Pasteur, Paris, 75724, cedex 15, France
    G. Courtois, S. Yamaoka & A. Israël
  3. Department of Molecular Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany
    Nina S. Heiss, S. M. Klauck, P. Kioschis, S. Wiemann & A. Poustka
  4. International Institute of Genetics and Biophysics, C.N.R. Via G. Marconi, 10, Naples , 80125, Italy
    Teresa Esposito, T. Bardaro, F. Gianfrancesco, A. Ciccodicola & M. D'Urso
  5. Wellcome Trust Centre for Molecular Mechanisms of Disease and University of Cambridge Department of Medicine Addenbrooke's Hospital, Hill Road, Cambridge, CB2 2XY, UK
    Hayley Woffendin, T. Jakins & S. J. Kenwrick
  6. St Mary's Hospital, Whitworth Park, Manchester, M13 OJH, UK
    D. Donnai & H. Stewart
  7. Departments of Molecular and Human Genetics,
    Swaroop Aradhya, R. A. Lewis & D. L. Nelson
  8. Dermatology,
    M. Levy
  9. Ophthalmology, Baylor College of Medicine , Houston, 77030, Texas, USA
    T. Yamagata & R. A. Lewis

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The International Incontinentia Pigmenti (IP) Consortium

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The International Incontinentia Pigmenti (IP) Consortium. Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti.Nature 405, 466–472 (2000). https://doi.org/10.1038/35013114

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