NF-κB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications.
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.
INSERM U781, Département de Génétique et de Radiologie Pédiatrique, Fondation IMAGINE, Université Paris Descartes, Hôpital Necker-Enfants Malades, 149 Rue de Sèvres, Paris, France.
Orianne
O
Philippe
Marlène
M
Rio
Valérie
V
Malan
Hilde
H
Van Esch
Geneviève
G
Baujat
Nadia
N
Bahi-Buisson
Vassili
V
Valayannopoulos
Roseline
R
Gesny
Jean-Paul
JP
Bonnefont
Arnold
A
Munnich
Guy
G
Froyen
Jeanne
J
Amiel
Nathalie
N
Boddaert
Laurence
L
Colleaux
D001369:Axons / Q000378:metabolism; D001921:Brain / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism / Q000503:physiopathology; D058674:Chromosome Duplication / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D019066:Facies; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018810:Magnetic Resonance Angiography; D008297:Male; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D011859:Radiography; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism; D025064:Sex Chromosome Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction
C491731:IKBKG protein, human; D016328:NF-kappa B; D051550:I-kappa B Kinase