Differential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation.

Dysregulated secretion in neutrophil leukocytes associates with human inflammatory disease. The exocytosis response to triggering stimuli is sequential; gelatinase granules modulate the initiation of the innate immune response, followed by the release of pro-inflammatory azurophilic granules, requiring stronger stimulation. Exocytosis requires actin depolymerization which is actively counteracted under non-stimulatory conditions.

Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male.

De novo somatic mutations are well documented in diseases such as neoplasia but are rarely reported in rare diseases. Hovewer, severe genetic diseases that are not compatible with embryonic development are caused exclusively by deleterious mutations that could only be found as mosaic and not as inherited mutations. We will review here the paradigmatic case of Incontinentia Pigmenti, a rare X-linked dominant disease caused by deficiency of the NEMO (also called IKKgamma) protein, which plays a pivotal role in tissue homeostasis.

Methods to Study the Effect of IKK Inhibition on TNF-Inducing Apoptosis and Necroptosis in Cultured Cells.

The engagement of TNF on TNFR can result in cell survival or cell death depending on the different complex formation downstream this interaction. Here we describe reagents and assay procedures that can be used to study caspase-independent cell death (necroptosis) in cultured cells, in response to pharmacological interventions with NF-kappaB and death inhibitors. We provide protocol to detect death-specific proteins using immunoblot and to dissect necrosome complex by sequential co-immunoprecipitation of death-specific components during necroptosis.

Author Correction: Pro-inflammatory cytokines activate hypoxia-inducible factor 3α via epigenetic changes in mesenchymal stromal/stem cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Life, death, and autophagy in cancer: NF-κB turns up everywhere.

Escaping programmed cell death is a hallmark of cancer. NF-κB transcription factors are key regulator of cell survival and aberrant NF-κB signaling has been involved in the pathogenesis of most human malignancies. Although NF-κB is best known for its antiapoptotic role, other processes regulating the life/death balance, such as autophagy and necroptosis, seem to network with NF-κB.

The Incontinentia Pigmenti Genetic Biobank: study design and cohort profile to facilitate research into a rare disease worldwide.

Incontinentia pigmenti (IP; OMIM#308300) is a rare genetic disease resulting in neuroectodermal defects, which can lead to disability. At present, there is neither definitive cure available nor are there any sufficiently reliable insights to predict the severity of the disease. We launched the Incontinentia Pigmenti Genetic Biobank (IPGB) project ( http://www.

Pro-inflammatory cytokines activate hypoxia-inducible factor 3α via epigenetic changes in mesenchymal stromal/stem cells.

Human mesenchymal stromal/stem cells (hMSCs) emerged as a promising therapeutic tool for ischemic disorders, due to their ability to regenerate damaged tissues, promote angiogenesis and reduce inflammation, leading to encouraging, but still limited results. The outcomes in clinical trials exploring hMSC therapy are influenced by low cell retention and survival in affected tissues, partially influenced by lesion's microenvironment, where low oxygen conditions (i.e.

Unusual Father-to-Daughter Transmission of Incontinentia Pigmenti Due to Mosaicism in IP Males.

Incontinentia pigmenti (IP; Online Mendelian Inheritance in Man catalog #308300) is an X-linked dominant ectodermal disorder caused by mutations of the inhibitor of κ polypeptide gene enchancer in B cells, kinase γ ()/ nuclear factor κB, essential modulator () gene. Hemizygous loss-of-function (LoF) mutations are lethal in males, thus patients are female, and the disease is always transmitted from an IP-affected mother to her daughter. We present 2 families with father-to-daughter transmission of IP and provide for the first time molecular evidence that the combination of somatic and germ-line mosaicism for loss of function mutations in IP males resulted in the transmission of the disease to a female child.

NEMO regulates a cell death switch in TNF signaling by inhibiting recruitment of RIPK3 to the cell death-inducing complex II.

Incontinentia Pigmenti (IP) is a rare X-linked disease characterized by early male lethality and multiple abnormalities in heterozygous females. IP is caused by NF-κB essential modulator (NEMO) mutations. The current mechanistic model suggests that NEMO functions as a crucial component mediating the recruitment of the IκB-kinase (IKK) complex to tumor necrosis factor receptor 1 (TNF-R1), thus allowing activation of the pro-survival NF-κB response.

Cognitive-behavioural phenotype in a group of girls from 1.2 to 12 years old with the Incontinentia Pigmenti syndrome: Recommendations for clinical management.

Incontinentia Pigmenti (IP, OMIM#308300) is a rare X-linked genomic disorder (about 1,400 cases) that affects the neuroectodermal tissue and Central Nervous System (CNS). The objective of this study was to describe the cognitive-behavioural profile in children in order to plan a clinical intervention to improve their quality of life. A total of 14 girls (age range: from 1 year and 2 months to 12 years and 10 months) with IP and the IKBKG/NEMO gene deletion were submitted to a cognitive assessment including intelligence scales, language and visuo-spatial competence tests, learning ability tests, and a behavioural assessment.

B cells from nuclear factor kB essential modulator deficient patients fail to differentiate to antibody secreting cells in response to TLR9 ligand.

Hypohidrotic ectodermal dysplasia (HED) consists of disorders resulting from molecular alterations of ectodysplasin-A (EDA) pathway. Hypomorphic mutations in NF-kB essential modulator, downstream EDA, result in HED with immunodeficiency (HED-ID), characterized by susceptibility to encapsulated pyogenic bacteria infections. Increased susceptibility to pneumococcal infections and poor response to polysaccharide antigens are associated with defect in T-independent B-cell immunity.

EDA-ID and IP, two faces of the same coin: how the same IKBKG/NEMO mutation affecting the NF-κB pathway can cause immunodeficiency and/or inflammation.

Anhidrotic Ectodermal Dysplasia with ImmunoDeficiency (EDA-ID, OMIM 300291) and Incontinentia Pigmenti (IP, OMIM 308300) are two rare diseases, caused by mutations of the IKBKG/NEMO gene. The protein NEMO/IKKγ is essential for the NF-κB activation pathway, involved in a variety of physiological and cellular processes, such as immunity, inflammation, cell proliferation, and survival. A wide spectrum of IKBKG/NEMO mutations have been identified so far, and, on the basis of their effect on NF-κB activation, they are considered hypomorphic or amorphic (loss of function) mutations.

COMMD7 as a novel NEMO interacting protein involved in the termination of NF-κB signaling.

NEMO/IKKγ is the regulatory subunit of the IκB Kinase (IKK) complex, required for the activation of the NF-κB pathway, which is involved in a variety of key processes, including immunity, inflammation, differentiation, and cell survival. Termination of NF-κB activity on specific -κB responsive genes, which is crucial for the resolution of inflammatory responses, can be achieved by direct degradation of the chromatin-bound NF-κB subunit RelA/p65, a process mediated by a protein complex that contains Copper Metabolism Murr1 Domain 1 (COMMD1). In this study, we identify COMMD7, another member of the COMMDs protein family, as a novel NEMO-interacting protein.

Incontinentia pigmenti: report on data from 2000 to 2013.

We report here on the building-up of a database of information related to 386 cases of Incontinentia Pigmenti collected in a thirteen-year activity (2000-2013) at our centre of expertise. The database has been constructed on the basis of a continuous collection of patients (27.6/year), the majority diagnosed as sporadic cases (75.

Incontinentia pigmenti: learning disabilities are a fundamental hallmark of the disease.

Studies suggest that genetic factors are associated with the etiology of learning disabilities. Incontinentia Pigmenti (IP, OMIM#308300), which is caused by mutations of the IKBKG/NEMO gene, is a rare X-linked genomic disorder (1:10000/20:000) that affects the neuroectodermal tissues. It always affects the skin and sometimes the hair, teeth, nails, eyes and central nervous system (CNS).

Insight into IKBKG/NEMO locus: report of new mutations and complex genomic rearrangements leading to incontinentia pigmenti disease.

Incontinentia pigmenti (IP) is an X-linked-dominant Mendelian disorder caused by mutation in the IKBKG/NEMO gene, encoding for NEMO/IKKgamma, a regulatory protein of nuclear factor kappaB (NF-kB) signaling. In more than 80% of cases, IP is due to recurrent or nonrecurrent deletions causing loss-of-function (LoF) of NEMO/IKKgamma. We review how the local architecture of the IKBKG/NEMO locus with segmental duplication and a high frequency of repetitive elements favor de novo aberrant recombination through different mechanisms producing genomic microdeletion.

The R156H variation in IL-12Rβ1 is not a mutation.

Palamaro et al. describe a child with recurrent bronchopneumonia and very high IgE levels in which a variation, R156H, was found in the IL12RB1 gene that encodes the IL-12Rβ1 chain. Based on the absence of this variation in 50 unrelated individuals they conclude it is a mutation.

A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX.

Intellectual disability (ID) and epilepsy often occur together and have a dramatic impact on the development and quality of life of the affected children. Polyalanine (polyA)-expansion-encoding mutations of aristaless-related homeobox (ARX) cause a spectrum of X-linked ID (XLID) diseases and chronic epilepsy, including infantile spasms. We show that lysine-specific demethylase 5C (KDM5C), a gene known to be mutated in XLID-affected children and involved in chromatin remodeling, is directly regulated by ARX through the binding in a conserved noncoding element.