Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura

Ramírez-Alejo, Noé; Alcántara-Montiel, Julio C.; Yamazaki‐Nakashimada, Marco Antonio; Durán‐McKinster, Carola; Valenzuela-León, Paola Carolina; Rivas-Larrauri, Francisco; Cedillo‐Barrón, Leticia; Hernández‐Rivas, Rosaura; Santos‐Argumedo, Leopoldo

doi:10.1016/j.clim.2015.06.007

Cited by 12 publications

(13 citation statements)

References 29 publications

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“…P1 ( IKBKG p.R63Q) suffered with Evans syndrome, colitis and granulomatous hepatitis. Autoimmune haemolytic anaemia and immune thrombocytopenia have both been reported in IKBKG deficiency, and colitis is a common inflammatory complication 12 , 13 , 14 . Hepatic granuloma have been only been reported in hypofunctional IKBKG due to disseminated mycobacterial infection 13 .…”

Section: Discussionmentioning

confidence: 99%

“…Autoimmune haemolytic anaemia and immune thrombocytopenia have both been reported in IKBKG deficiency, and colitis is a common inflammatory complication. [12][13][14] Hepatic granuloma have been only been reported in hypofunctional IKBKG due to disseminated mycobacterial infection. 13 A liver biopsy Autoimmunity in a PID cohort W Rae et al performed on P1 found no evidence of mycobacteria or other pathogens, suggesting that the granuloma are sterile and due to immune dysregulation.…”

Section: Discussionmentioning

confidence: 99%

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Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

et al. 2017

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Primary immunodeficiencies (PIDs) are rare inborn errors of immunity that have a heterogeneous phenotype that can include severe susceptibility to life-threatening infections from multiple pathogens, unique sensitivity to a single pathogen, autoimmune/inflammatory (AI/I) disease, allergies and/or malignancy. We present a diverse cohort of monogenic PID patients with and without AI/I diseases who underwent clinical, genetic and immunological phenotyping. Novel pathogenic variants were identified in IKBKG, CTLA4, NFKB1, GATA2, CD40LG and TAZ as well as previously reported pathogenic variants in STAT3, PIK3CD, STAT1, NFKB2 and STXBP2. AI/I manifestations were frequently encountered in PIDs, including at presentation. Autoimmunity/inflammation was multisystem in those effected, and regulatory T cell (Treg) percentages were significantly decreased compared with those without AI/I manifestations. Prednisolone was used as the first-line immunosuppressive agent in all cases, however steroid monotherapy failed long-term control of autoimmunity/inflammation in the majority of cases and additional immunosuppression was required. Patients with multisystem autoimmunity/inflammation should be investigated for an underlying PID, and in those with PID early assessment of Tregs may help to assess the risk of autoimmunity/inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

et al. 2017

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“…1,2,[5][6][7] XR-EDA-ID is perhaps the most heterogeneous PID yet identified at the allelic, immunological, and clinical levels, 13 making clinical care of the patients particularly challenging. The precise mechanisms underlying the infectious and inflammatory phenotypes remain unknown, but hematopoietic stem cell transplantation (HSCT) has been performed in 29 children with IKBKG mutations 9,10,12,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] (personal communications [see supplemental Methods, available on the Blood Web site]). These children probably account for less than 10% of the children with XR-EDA-ID reported worldwide.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations

Miot

Imai

et al. 2017

Blood

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X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of mutations.

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“…[107][108][109][110] LOF mutations in the IKBKG locus, which encodes NEMO, cause X-linked EDA-ID diseases. These mutations include X420W, R175P, L227P, A288G, D311N, C417F, and C417R, which result in truncated NEMO proteins and repress NF-kB activation.…”

Section: Gof Ikba Mutations and Loss-of-function (Lof) Ikbkg Mutationmentioning

confidence: 99%

“…The prevalence of the X‐linked recessive type of EDA‐ID is estimated to be 1 in 250 000 individuals . LOF mutations in the IKBKG locus, which encodes NEMO, cause X‐linked EDA‐ID diseases.…”

Section: Gof Ikba Mutations and Loss‐of‐function (Lof) Ikbkg Mutationmentioning

confidence: 99%

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

Zhu

2018

BioEssays

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A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell-mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IkB kinase α (IKKα) is one subunit of the IKK complex required for NF-kB activation. IKK/NF-kB is essential for central tolerance establishment by regulating the development of medullary thymic epithelial cells (mTECs) that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-kB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-kB components, through mTEC (stroma), T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-kB in these diseases.

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Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura

Cited by 12 publications

References 29 publications

Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

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