NEMO, NFκB signaling and incontinentia pigmenti

Nelson, David L.

doi:10.1016/j.gde.2006.04.013

Cited by 81 publications

(48 citation statements)

References 62 publications

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“…Given the high percentage of sporadic cases observed (around 65% according to data reported by Smahi et al [2000], Aradhya et al [2001c], Fusco et al [2004], and from present data; see also Nelson [2006] for a review), we suspect that the prevalence of IP (1:10,000/20,000) has been underestimated. In addition, most of the IKBKG small mutations (37/46) are private except for nine mutations that have been found repeatedly (Table 1).…”

Section: Mutations Of Ikbkg Ikbkg Mutations In Femalesmentioning

confidence: 47%

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

et al. 2008

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Communicated by Andrew O.M. WilkieMutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) essential modulator (NEMO), gene are the most common single cause of incontinentia pigmenti (IP) in females and anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males. The IKBKG gene, located in the Xq28 chromosomal region, encodes for the regulatory subunit of the inhibitor of kappaB (IkB) kinase (IKK) complex required for the activation of the NF-kB pathway. Therefore, the remarkably heterogeneous and often severe clinical presentation reported in IP is due to the pleiotropic role of this signaling transcription pathway. A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts for 60 to 80% of IP-causing mutations. Besides the IKBKG rearrangement found in IP females (which is lethal in males), a total of 69 different small mutations (missense, frameshift, nonsense, and splice-site mutations) have been reported, including 13 novel ones in this work. The updated distribution of all the IP-and EDA-ID-causing mutations along the IKBKG gene highlights a secondary hotspot mutation in exon 10, which contains only 11% of the protein. Furthermore, familial inheritance analysis revealed an unexpectedly high incidence of sporadic cases (465%). The sum of the observations can aid both in determining the molecular basis of IP and EDA-ID allelic diseases, and in genetic counseling in affected families. Hum Mutat 29(5), [595][596][597][598][599][600][601][602][603][604] 2008.

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Section: Mutations Of Ikbkg Ikbkg Mutations In Femalesmentioning

confidence: 47%

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

et al. 2008

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“…These lesions subsequently become hyperkeratotic followed by the development of hyperpigmented patches, due to the accumulation of melanin in the dermis. In the last stage, phagocytes clear up the free melanin, leaving areas of dermal scarring with atrophic skin that also displays lack of skin appendages such as hair follicles or sweat glands [76].…”

Section: Keratinocyte-restricted Inhibition Of Nf-κb Induces Skin Infmentioning

confidence: 99%

NF-κB in the regulation of epithelial homeostasis and inflammation

2010

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The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.

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“…The perinatal incidence of IP is estimated at a level of 1 to 50 000 births, but it is probably higher. The disease is difficult to diagnose by non-dermatologists as it is sometimes confused with usually infectious conditions, such as HSV, BI or erythema toxicum [1,17,21]. The underlying defect in IP is a mutation in the essential modulator gene (NEMO), which results in the loss of activity of the regulatory component of the IκB kinase (IKK) complex encoded by the NEMO/IKKγ gene.…”

Section: Discussionmentioning

confidence: 99%

“…The underlying defect in IP is a mutation in the essential modulator gene (NEMO), which results in the loss of activity of the regulatory component of the IκB kinase (IKK) complex encoded by the NEMO/IKKγ gene. Deletion of exons 4 -10 is observed in 80% of patients with IP [8,17,21]. Thus, nonfunctional IKK abolishes activity of nuclear factor-κ B (NFκB), preventing the transcription of various target genes.…”

Section: Discussionmentioning

confidence: 99%

Bloch-Sulzberger syndrome: a

Rosińska-Więckowicz¹,

Czarnecka‐Operacz²

2012

pdia

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A b s t r a c tIncontinentia pigmenti (IP, Bloch-Sulzberger syndrome) is a very rare genodermatosis characterized by typical skin lesions accompanied by dental, central nervous system, bone and ocular abnormalities. Incontinentia pigmenti is usually observed among women, as this X-linked dominantly inherited disorder is lethal in males. The hallmark feature of IP is cutaneous eruption along the lines of Blaschko, usually accompanied by neurological disorders. Apart from clinical features of the disease, skin biopsy is the best diagnostic tool to confirm the diagnosis. We present a case of a newborn with typical vesicular and then verrucous lesions affecting the lower legs. K Ke ey y w wo or rd ds s: : incontinentia pigmenti, Bloch-Sulzberger syndrome.

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NEMO, NFκB signaling and incontinentia pigmenti

Cited by 81 publications

References 62 publications

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

NF-κB in the regulation of epithelial homeostasis and inflammation

Bloch-Sulzberger syndrome: a

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