Abstract
One of the key signals regulating peripheral myelin formation by Schwann cell is the activation of the transcription factor NF-κB. Yet, whether NF-κB exerts similar functions in central myelin formation by oligodendrocytes remains largely unknown. We previously reported white matter abnormalities with unusual discordance between T2 and FLAIR sequences in a patient with intellectual disability and defective NF-κB signalling. These observations prompted us to hypothesise that NF-κB signalling may have a role in the axon myelination process of central neurons. We report here on five male patients with Xq28 duplications encompassing MECP2, three of which presented white matter anomalies on brain MRI. Array-CGH and FISH analyses demonstrated that brain abnormalities correlate with additional copies of the IKBKG, a gene encoding a key regulator of NF-κB activation. Quantitative RT-PCR experiments and κB-responsive reporter gene assays provide evidence that IKBKG overexpression causes impaired NF-κB signalling in skin fibroblasts derived from patients with white matter anomalies. These data further support the role of NF-κB signalling in astroglial cells for normal myelin formation of the central nervous system.
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Acknowledgements
We are grateful to the patients for their participation in the study. We sincerely acknowledge Elodie Bal for technical assistance and Sylvain Hanein for the gift of the SH-SY5 cell line. This study has been supported by the Centre National de la Recherche Scientifique (CNRS), the Agence Nationale de la Recherche (Grant NOANR-08-MNP-010) and the Ministère de la Recherche et de l’Enseignement Supérieur.
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Philippe, O., Rio, M., Malan, V. et al. NF-κB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications. Eur J Hum Genet 21, 195–199 (2013). https://doi.org/10.1038/ejhg.2012.140
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DOI: https://doi.org/10.1038/ejhg.2012.140
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