Non-Skewed X-inactivation Results in NF-κB Essential Modulator (NEMO) Δ-exon 5-autoinflammatory Syndrome (NEMO-NDAS) in a Female with Incontinentia Pigmenti.
Autoinflammation
Immunodeficiency
Incontinentia pigmenti
NEMO
Non-skewed X-inactivation
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
12 Sep 2024
12 Sep 2024
Historique:
received:
01
02
2024
accepted:
30
08
2024
medline:
12
9
2024
pubmed:
12
9
2024
entrez:
12
9
2024
Statut:
epublish
Résumé
Genetic hypomorphic defects in X chromosomal IKBKG coding for the NF-κB essential modulator (NEMO) lead to ectodermal dysplasia and immunodeficiency in males and the skin disorder incontinentia pigmenti (IP) in females, respectively. NF-κB essential modulator (NEMO) Δ-exon 5-autoinflammatory syndrome (NEMO-NDAS) is a systemic autoinflammatory disease caused by alternative splicing and increased proportion of NEMO-Δex5. We investigated a female carrier presenting with IP and NEMO-NDAS due to non-skewed X-inactivation. IKBKG transcripts were quantified in peripheral blood mononuclear cells isolated from the patient, her mother, and healthy controls using RT-PCR and nanopore sequencing. Corresponding proteins were analyzed by western blotting and flow cytometry. Besides toll-like receptor (TLR) and tumor necrosis factor (TNF) signaling, the interferon signature, cytokine production and X-inactivation status were investigated. IP and autoinflammation with recurrent fever, oral ulcers, hepatitis, and neutropenia, but no immunodeficiency was observed in a female patient. Besides moderately reduced NEMO signaling function, type I interferonopathy, and elevated IL-18 and CXCL10 were found. She and her mother both carried the heterozygous variant c.613 C > T p.(Gln205*) in exon 5 of IKBKG previously reported in NEMO-deficient patients. However, X-inactivation was skewed in the mother, but not in the patient. Alternative splicing led to increased ratios of NEMO-Dex5 over full-length protein in peripheral blood cell subsets causing autoinflammation. Clinical symptoms partially resolved under treatment with TNF inhibitors. Non-skewed X-inactivation can lead to NEMO-NDAS in females with IP carrying hypomorphic IKBKG variants due to alternative splicing and increased proportions of NEMO-∆ex5.
Identifiants
pubmed: 39264518
doi: 10.1007/s10875-024-01799-2
pii: 10.1007/s10875-024-01799-2
doi:
Substances chimiques
I-kappa B Kinase
EC 2.7.11.10
IKBKG protein, human
0
Cytokines
0
Types de publication
Journal Article
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
1Informations de copyright
© 2024. The Author(s).
Références
Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, et al. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell. 1998;93(7):1231–40.
doi: 10.1016/S0092-8674(00)81466-X
pubmed: 9657155
Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986;47(6):921–8.
doi: 10.1016/0092-8674(86)90807-X
pubmed: 3096580
Picard C, Casanova JL, Puel A. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IkappaBalpha deficiency. Clin Microbiol Rev. 2011;24(3):490–7.
doi: 10.1128/CMR.00001-11
pubmed: 21734245
pmcid: 3131061
Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, et al. IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex. Mol Cell Biol. 1999;19(2):1526–38.
doi: 10.1128/MCB.19.2.1526
pubmed: 9891086
pmcid: 116081
Rothwarf DM, Zandi E, Natoli G, Karin M. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature. 1998;395(6699):297–300.
doi: 10.1038/26261
pubmed: 9751060
Shifera AS. The zinc finger domain of IKKgamma (NEMO) protein in health and disease. J Cell Mol Med. 2010;14(10):2404–14.
doi: 10.1111/j.1582-4934.2010.01054.x
pubmed: 20345847
pmcid: 3823158
Zhao T, Yang L, Sun Q, Arguello M, Ballard DW, Hiscott J, et al. The NEMO adaptor bridges the nuclear factor-kappab and interferon regulatory factor signaling pathways. Nat Immunol. 2007;8(6):592–600.
doi: 10.1038/ni1465
pubmed: 17468758
Shin CH, Choi DS. Essential roles for the non-canonical IkappaB kinases in linking inflammation to Cancer, obesity, and diabetes. Cells. 2019;8(2).
Hanson EP, Monaco-Shawver L, Solt LA, Madge LA, Banerjee PP, May MJ, et al. Hypomorphic nuclear factor-kappab essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol. 2008;122(6):1169–e7716.
doi: 10.1016/j.jaci.2008.08.018
pubmed: 18851874
pmcid: 2710968
Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet. 2000;67(6):1555–62.
doi: 10.1086/316914
pubmed: 11047757
pmcid: 1287930
Pachlopnik Schmid JM, Junge SA, Hossle JP, Schneider EM, Roosnek E, Seger RA, et al. Transient hemophagocytosis with deficient cellular cytotoxicity, monoclonal immunoglobulin M gammopathy, increased T-cell numbers, and hypomorphic NEMO mutation. Pediatrics. 2006;117(5):e1049–56.
doi: 10.1542/peds.2005-2062
pubmed: 16636116
Heller S, Kolsch U, Magg T, Kruger R, Scheuern A, Schneider H, et al. T cell impairment is predictive for a severe clinical course in NEMO Deficiency. J Clin Immunol. 2020;40(3):421–34.
doi: 10.1007/s10875-019-00728-y
pubmed: 31965418
Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. Int Incontinentia Pigmenti (IP) Consortium Nat. 2000;405(6785):466–72.
Kosaki K, Shimasaki N, Fukushima H, Hara M, Ogata T, Matsuo N. Female patient showing hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). Am J Hum Genet. 2001;69(3):664–6.
doi: 10.1086/323003
pubmed: 11484156
pmcid: 1235496
Martinez-Pomar N, Munoz-Saa I, Heine-Suner D, Martin A, Smahi A, Matamoros N. A new mutation in exon 7 of NEMO gene: late skewed X-chromosome inactivation in an incontinentia pigmenti female patient with immunodeficiency. Hum Genet. 2005;118(3–4):458–65.
doi: 10.1007/s00439-005-0068-y
pubmed: 16228229
Ohnishi H, Kishimoto Y, Taguchi T, Kawamoto N, Nakama M, Kawai T, et al. Immunodeficiency in two female patients with Incontinentia Pigmenti with heterozygous NEMO mutation diagnosed by LPS unresponsiveness. J Clin Immunol. 2017;37(6):529–38.
doi: 10.1007/s10875-017-0417-3
pubmed: 28702714
Mou W, Zhao Z, Gao L, Fu L, Li J, Jiao A, et al. An Atypical Incontinentia Pigmenti Female with Persistent Mucocutaneous Hyperinflammation and Immunodeficiency caused by a novel germline IKBKG missense mutation. J Clin Immunol. 2023;43(8):2165–80.
doi: 10.1007/s10875-023-01564-x
pubmed: 37831401
Lin HK, Fu LS. Concurrence of Incontinentia Pigmenti and Behcet’s Disease. J Chin Med Assoc. 2010;73(5):275–8.
doi: 10.1016/S1726-4901(10)70060-5
pubmed: 20685598
Marquez Balbas G, Gonzalez-Ensenat MA, Vicente A, Creus-Vila L, Anton J, Umbert-Millet P. Incontinentia pigmenti and bipolar aphthosis: an unusual combination. ISRN Dermatol. 2011;2011:814186.
doi: 10.5402/2011/814186
pubmed: 22363861
pmcid: 3262544
Klemann C, Pannicke U, Morris-Rosendahl DJ, Vlantis K, Rizzi M, Uhlig H, et al. Transplantation from a symptomatic carrier sister restores host defenses but does not prevent colitis in NEMO deficiency. Clin Immunol. 2016;164:52–6.
doi: 10.1016/j.clim.2016.01.010
pubmed: 26812624
pmcid: 6101191
de Jesus AA, Hou Y, Brooks S, Malle L, Biancotto A, Huang Y, et al. Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. J Clin Invest. 2020;130(4):1669–82.
doi: 10.1172/JCI129301
pubmed: 31874111
pmcid: 7108905
Lee Y, Wessel AW, Xu J, Reinke JG, Lee E, Kim SM et al. Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype. J Clin Invest. 2022;132(6).
Hegazy S, Marques MC, Canna SW, Goldbach-Mansky R, de Jesus AA, Reyes-Mugica M, et al. NEMO-NDAS: a panniculitis in the Young representing an autoinflammatory disorder in disguise. Am J Dermatopathol. 2022;44(6):e64–6.
doi: 10.1097/DAD.0000000000002144
pubmed: 35120036
pmcid: 9117406
Wolf C, Bruck N, Koss S, Griep C, Kirschfink M, Palm-Beden K, et al. Janus kinase inhibition in complement component 1 deficiency. J Allergy Clin Immunol. 2020;146(6):1439–e425.
doi: 10.1016/j.jaci.2020.04.002
pubmed: 32325142
Miyazawa H, Wada T. Reversion mosaicism in primary Immunodeficiency diseases. Front Immunol. 2021;12:783022.
doi: 10.3389/fimmu.2021.783022
pubmed: 34868061
pmcid: 8635092
de Jesus ATS, Lin B, Mitchell J, Karlins E, Oler A, Alehashemi S, Kahle D, Honer K, Souto Adeva G, Hanson E, Montealegre Sanchez G, Khojah A, Moran T, Wu E, Scott C, Leahy T, MacDermott E, Killeen O, Arkachaisri T, Gucev Z, Phillippi K, Mammadova V, Nasrullayeva G, Goldbach-Mansky R. Splice site variants in IKBKG, Encoding NEMO, detected by a Customized Analysis of Next-Generation Sequencing Data Cause an early-onset Autoinflammatory Syndrome of Panniculitis and cytopenias in male and female patients [abstract]. Arthritis Rheumatol 2020.
Hai T, Yeung ML, Wood TG, Wei Y, Yamaoka S, Gatalica Z, et al. An alternative splice product of IkappaB kinase (IKKgamma), IKKgamma-delta, differentially mediates cytokine and human T-cell leukemia virus type 1 tax-induced NF-kappaB activation. J Virol. 2006;80(9):4227–41.
doi: 10.1128/JVI.80.9.4227-4241.2006
pubmed: 16611882
pmcid: 1472011
Jorgensen SE, Bottger P, Kofod-Olsen E, Holm M, Mork N, Orntoft TF, et al. Ectodermal dysplasia with immunodeficiency caused by a branch-point mutation in IKBKG/NEMO. J Allergy Clin Immunol. 2016;138(6):1706–9. e4.
doi: 10.1016/j.jaci.2016.05.030
pubmed: 27477329
Orstavik KH, Kristiansen M, Knudsen GP, Storhaug K, Vege A, Eiklid K, et al. Novel splicing mutation in the NEMO (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome inactivation. Am J Med Genet A. 2006;140(1):31–9.
doi: 10.1002/ajmg.a.31026
pubmed: 16333836
Brownell J, Bruckner J, Wagoner J, Thomas E, Loo YM, Gale M Jr., et al. Direct, interferon-independent activation of the CXCL10 promoter by NF-kappaB and interferon regulatory factor 3 during hepatitis C virus infection. J Virol. 2014;88(3):1582–90.
doi: 10.1128/JVI.02007-13
pubmed: 24257594
pmcid: 3911583
Alehashemi S, Goldbach-Mansky R. Human autoinflammatory diseases mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome dysregulation updates on diagnosis, treatment, and the respective roles of IL-1 and IL-18. Front Immunol. 2020;11:1840.
doi: 10.3389/fimmu.2020.01840
pubmed: 32983099
pmcid: 7477077
Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46(10):1140–6.
doi: 10.1038/ng.3089
pubmed: 25217959
pmcid: 4177369
Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, et al. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet. 2014;46(10):1135–9.
doi: 10.1038/ng.3066
pubmed: 25217960
pmcid: 4177367
Weiss ES, Girard-Guyonvarc’h C, Holzinger D, de Jesus AA, Tariq Z, Picarsic J, et al. Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood. 2018;131(13):1442–55.
doi: 10.1182/blood-2017-12-820852
pubmed: 29326099
pmcid: 5877443
Liu T, Zhang L, Joo D, Sun SC. NF-kappaB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023.
doi: 10.1038/sigtrans.2017.23
pubmed: 29158945
pmcid: 5661633
van Loo G, Bertrand MJM. Death by TNF: a road to inflammation. Nat Rev Immunol. 2023;23(5):289–303.
doi: 10.1038/s41577-022-00792-3
pubmed: 36380021
Chen L, Zhang X, Ou Y, Liu M, Yu D, Song Z, et al. Advances in RIPK1 kinase inhibitors. Front Pharmacol. 2022;13:976435.
doi: 10.3389/fphar.2022.976435
pubmed: 36249746
pmcid: 9554302
Miot C, Imai K, Imai C, Mancini AJ, Kucuk ZY, Kawai T, et al. Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations. Blood. 2017;130(12):1456–67.
doi: 10.1182/blood-2017-03-771600
pubmed: 28679735
pmcid: 5609334
Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S, et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature. 2007;446(7135):557–61.
doi: 10.1038/nature05698
pubmed: 17361131