NF-κB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications

Abstract

One of the key signals regulating peripheral myelin formation by Schwann cell is the activation of the transcription factor NF-jB. Yet, whether NF-jB 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-jB signalling. These observations prompted us to hypothesise that NF-jB 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-jB activation. Quantitative RT-PCR experiments and jB-responsive reporter gene assays provide evidence that IKBKG overexpression causes impaired NF-jB signalling in skin fibroblasts derived from patients with white matter anomalies. These data further support the role of NF-jB signalling in astroglial cells for normal myelin formation of the central nervous system.

Systematic review of central nervous system anomalies in incontinentia pigmenti

“…However, other brain imaging and pathoanatomical studies fail to show a relationship between brain abnormalities and vascular patterns [14,26]. Brain infarcts found in IP patients [30-32] supported the hypothesis of vascular pathogenesis of CNS lesions in IP, whereas findings of brain atrophy [11,20], corpus callosum lesions [14,20], disorder of myelination [27,33] and lack of relationship between brain abnormalities and vascular patterns [14,26] supported the hypothesis of disorder of the NF-κB metabolic pathway in neurons and glia cells as a pathogenetic mechanism.…”

Large national series of patients with Xq28 duplication involving MECP2: Delineation of brain MRI abnormalities in 30 affected patients

“…We can thus note that the brain MRI abnormalities we observed in our series did not seem different from those observed in patients with non‐syndromic non‐progressive ID. Moreover, agenesis/hypoplasia of the corpus callosum, posterior fossa abnormalities, and hypomyelination can be observed in numerous malformative syndromes and thus do not provide any clues for the diagnosis of Xq28 duplication syndrome involving MECP2 [Guibaud and des Portes, ; Schell‐Apacik et al, ; Philippe et al, ].…”

“…Brain magnetic resonance imaging (MRI) abnormalities have rarely been described in patients with MECP2 duplication syndrome [Echenne et al, , Reardon et al, ; Honda et al, ; Philippe et al, ]. The goal of this article is to describe brain abnormalities observed on MRI in 30 patients carrying an Xq28 duplication involving MECP2 , and to seek a genotype‐imaging phenotype correlation.…”

Nuclear factor‐kappaB regulates multiple steps of gliogenesis in the developing murine cerebral cortex

“…Together, these results suggest that NF-κB inhibition leads to increased numbers of committed gliogenic NPCs that choose to activate an oligodendrocyte differentiation program. These observations implicate NF-κB in the negative regulation of both the initial decision to commit to glial cell development and the subsequent choice of whether or not to three out of five also exhibit defective CNS myelination (Philippe et al, 2013). This observation led to the suggestion that NF-κB is important for central nervous system (CNS) myelination, a possibility that was first suggested by the report that NF-κB activation is required for Schwann cell myelination (Chen et al, 2011;Nickols, Valentine, Kanwal, & Carter, 2003).…”

“…Philippe et al described five human patients carrying additional copies of the IKBKG gene (encoding NEMO, the regulatory subunit of the IKK complex), a genetic alteration resulting in functional impairment of NF‐κB signaling. These patients exhibit developmental brain abnormalities and mild mental retardation and, importantly, three out of five also exhibit defective CNS myelination (Philippe et al, ). This observation led to the suggestion that NF‐κB is important for central nervous system (CNS) myelination, a possibility that was first suggested by the report that NF‐κB activation is required for Schwann cell myelination (Chen et al, ; Nickols, Valentine, Kanwal, & Carter, ).…”