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

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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Figure 1: Amplification by RT–PCR of NEMO cDNA from IP patient cell lines.
Figure 2: Genomic structure of the NEMO gene and partial restriction map (H, HindIII; E, EcoRI).
Figure 3: Genomic rearrangement in IP patients.
Figure 4: Defective NF-κB activation 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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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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