A database for immunodeficiency due to mutations in nuclear factor kappa B pathway genes
Abstract
Nuclear factor kappa B (NFκB) pathway defects are associated with immunodeficiency; however, multiple phenotypes for mutations in genes encoding for NFκB proteins have been reported. We sought to create a database of published mutations in the genes encoding for IKKα and IKKβ and the regulatory subunit IKKγ, also referred to as NFκB essential modulator (NEMO). All published mutations were reviewed. The clinical and laboratory phenotypes were recorded and yearly updates of new mutations and phenotypes will be performed. Multiple immunodeficiency and infectious phenotypes were recorded particularly for patients with NEMO gene mutations. Even patients with the same NEMO mutation tended to have somewhat different phenotypes. In patients with primary immunodeficiency, the clinical phenotype may not direct the clinician to the genetic cause of the disease. Therefore, a comprehensive database will expand our knowledge and enhance the clinician’s ability to predict which gene mutation is the cause of the immunodeficiency. This database can assist clinicians in the diagnoses of patients with specific features of immunodeficiency.
Statement of novelty: A comprehensive database of published mutations in the genes encoding for IKKα, IKKβ, and IKKγ was created. This database may aid the clinician in recognizing specific immunodeficiency phenotypes.
Introduction
The nuclear factor kappa B (NFκB) family of transcription factors is essential for a variety of biological functions including response to stress, infection, and inflammation. The NFκB is normally found in the cytoplasm due to the effects of the inhibitor of NFκB, (IkB). Upon canonical stimulation of the NFκB pathway, the IκB components are phosphorylated by the IκB kinase (IKK) which is composed of 2 catalytic subunits (IKKα and IKKβ) and a regulatory subunit (IKKγ, also referred to as NEMO, NFκB essential modulator, IKBKG), leading to the degradation of the IκB which allows for translocation of the NFκB into the nucleus and transcription of pro-inflammatory genes (Gilmore 2006).
As expected, mutations within this pathway have a deleterious effect on susceptibility to malignancies, development, and the immune system. Mutations in genes encoding for NEMO, IκKα, and IKKβ cause a wide variety of immunodeficiency phenotypes. The NEMO gene is found at the Xq28 region, males born with hypomorphic mutations in the NEMO gene usually suffer from combined immunodeficiency with or without ectodermal dysplasia. Null mutations in males are lethal in utero and female carriers of mutations in the NEMO gene have a typical skin condition with streaks of hyperpigmentation known as incontinenta pigmenti. Diseases from mutations in IκKα and IKKβ are inherited in an autosomal recessive manner (Courtois and Gilmore 2006). We have created a database (Tables 1–3) of published mutations in NEMO, IκKα, and IKKβ and we show a wide clinical spectrum of immunodeficiency and infectious phenotypes. This database can aid the clinician in recognizing specific immunodeficiency phenotypes and promote the diagnosis of NFκB pathway defects.
Table 1:
Table 2:
Table 3:
REFERENCES
Abinun M., Spickett G., Appleton A.L., Flood T., and Cant A.J.1996. Anhidrotic ectodermal dysplasia associated with specific antibody deficiency. Eur. J. Pediatr. 155(2):146–147.
Aradhya S., Bardaro T., Galgoczy P., Yamagata T., Esposito T., Patlan H., Ciccodicola A., Munnich A., Kenwrick S., Platzer M., D’Urso M., and Nelson D.L.2001. Multiple pathogenic and benign genomic rearrangements occur at a 35 kb duplication involving the NEMO and LAGE2 genes. Hum. Mol. Genet. 10(22):2557–2567.
Brodeur S.R., Angelini F., Bacharier L.B., Blom A.M., Mizoguchi E., Fujiwara H., Plebani A., Notarangelo L.D., Dahlback B., Tsitsikov E., and Geha R.S.2003. C4b-binding protein (C4BP) activates B cells through the CD40 receptor. Immunity. 18(6):837–848.
Burns S.O., Plagnol V., Gutierrez B.M., Al Zahrani D., Curtis J., Gaspar M., Hassan A., Jones A.M., Malone M., Rampling D., McLatchie A., Doffinger R., Gilmour K.C., Henriquez F., Thrasher A.J., Gaspar H.B., and Nejentsev S.2014. Immunodeficiency and disseminated mycobacterial infection associated with homozygous nonsense mutation of IKKβ. J. Allergy Clin. Immunol. 134(1):215–218.
Carrol E.D., Gennery A.R., Flood T.J., Spickett G.P., and Abinun M.2003. Anhidrotic ectodermal dysplasia and immunodeficiency: The role of NEMO. Arch. Dis. Child. 88(4):340–341.
Courtois G. and Gilmore T.D.2006. Mutations in the NF-kappaB signaling pathway: Implications for human disease. Oncogene. 25(51):6831–6843.
Courtois G., Smahi A., Reichenbach J., Doffinger R., Cancrini C., Bonnet M., Puel A., Chable-Bessia C., Yamaoka S., Feinberg J., Dupuis-Girod S., Bodemer C., Livadiotti S., Novelli F., Rossi P., Fischer A., Israel A., Munnich A., Le Deist F., and Casanova J.L.2003. A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J. Clin. Invest. 112(7):1108–1115.
Dai Y.S., Liang M.G., Gellis S.E., Bonilla F.A., Schneider L.C., Geha R.S., and Orange J.S.2004. Characteristics of mycobacterial infection in patients with immunodeficiency and nuclear factor-kappaB essential modulator mutation, with or without ectodermal dysplasia. J. Am. Acad. Dermatol. 51(5):718–722.
Deering R.P. and Orange J.S.2006. Development of a clinical assay to evaluate toll-like receptor function. Clin. Vaccine Immunol. 13(1):68–76.
Devora G.A., Sun L., Chen Z., van Oers N.S., Hanson E.P., Orange J.S., and de la Morena M.T.2010. A novel missense mutation in the nuclear factor-kappaB essential modulator (NEMO) gene resulting in impaired activation of the NF-kappaB pathway and a unique clinical phenotype presenting as MRSA subdural empyema. J. Clin. Immunol. 30(6):881–885.
Doffinger R., Smahi A., Bessia C., Geissmann F., Feinberg J., Durandy A., Bodemer C., Kenwrick S., Dupuis-Girod S., Blanche S., Wood P., Rabia S.H., Headon D.J., Overbeek P.A., Le Deist F., Holland S.M., Belani K., Kumararatne D.S., Fischer A., Shapiro R., Conley M.E., Reimund E., Kalhoff H., Abinun M., Munnich A., Israel A., Courtois G., and Casanova J.L.2001. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat. Genet. 27(3):277–285.
Dupuis-Girod S., Corradini N., Hadj-Rabia S., Fournet J.C., Faivre L., Le Deist F., Durand P., Doffinger R., Smahi A., Israel A., Courtois G., Brousse N., Blanche S., Munnich A., Fischer A., Casanova J.L., and Bodemer C.2002. Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother. Pediatrics. 109(6):e97.
Filipe-Santos O., Bustamante J., Haverkamp M.H., Vinolo E., Ku C.L., Puel A., Frucht D.M., Christel K., von Bernuth H., Jouanguy E., Feinberg J., Durandy A., Senechal B., Chapgier A., Vogt G., de Beaucoudrey L., Fieschi C., Picard C., Garfa M., Chemli J., Bejaoui M., Tsolia M.N., Kutukculer N., Plebani A., Notarangelo L., Bodemer C., Geissmann F., Israel A., Veron M., Knackstedt M., Barbouche R., Abel L., Magdorf K., Gendrel D., Agou F., Holland S.M., and Casanova J.L.2006. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J. Exp. Med. 203(7):1745–1759.
Gilmore T.D.2006. Introduction to NF-kappaB: Players, pathways, perspectives. Oncogene. 25(51):6680–6684.
Hanson E.P., Monaco-Shawver L., Solt L.A., Madge L.A., Banerjee P.P., May M.J., and Orange J.S.2008. Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J. Allergy Clin. Immunol. 122(6):1169–1177.e16.
Haverkamp M.H., Arend S.M., Lindeboom J.A., Hartwig N.G., and van Dissel J.T.2004. Nontuberculous mycobacterial infection in children: A 2-year prospective surveillance study in the Netherlands. Clin. Infect. Dis. 39(4):450–456.
Holland S.M., Eisenstein E.M., Kuhns D.B., Turner M.L., Fleisher T.A., Strober W., and Gallin J.I.1994. Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma. A preliminary report. N. Engl. J. Med. 330(19):1348–1355.
Hubeau M., Ngadjeua F., Puel A., Israel L., Feinberg J., Chrabieh M., Belani K., Bodemer C., Fabre I., Plebani A., Boisson-Dupuis S., Picard C., Fischer A., Israel A., Abel L., Veron M., Casanova J.L., Agou F., and Bustamante J.2011. New mechanism of X-linked anhidrotic ectodermal dysplasia with immunodeficiency: Impairment of ubiquitin binding despite normal folding of NEMO protein. Blood. 118(4):926–935.
Imamura M., Kawai T., Okada S., Izawa K., Takachi T., Iwabuchi H., Yoshida S., Hosokai R., Kanegane H., Yamamoto T., Umezu H., Nishikomori R., Heike T., Uchiyama M., and Imai C.2011. Disseminated BCG infection mimicking metastatic nasopharyngeal carcinoma in an immunodeficient child with a novel hypomorphic NEMO mutation. J. Clin. Immunol. 31(5):802–810.
Jain A., Ma C.A., Liu S., Brown M., Cohen J., and Strober W.2001. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat. Immunol. 2(3):223–228.
Janssen R., van Wengen A., Hoeve M.A., ten Dam M., van der Burg M., van Dongen J., van de Vosse E., van Tol M., Bredius R., Ottenhoff T.H., Weemaes C., van Dissel J.T., and Lankester A.2004. The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. J. Exp. Med. 200(5):559–568.
Karakawa S., Okada S., Tsumura M., Mizoguchi Y., Ohno N., Yasunaga S., Ohtsubo M., Kawai T., Nishikomori R., Sakaguchi T., Takihara Y., and Kobayashi M.2011. Decreased expression in nuclear factor-kappaB essential modulator due to a novel splice-site mutation causes X-linked ectodermal dysplasia with immunodeficiency. J. Clin. Immunol. 31(5):762–772.
Karamchandani-Patel G., Hanson E.P., Saltzman R., Kimball C.E., Sorensen R.U., and Orange J.S.2011. Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels. Ann. Allergy Asthma Immunol. 107(1):50–56.
Kosaki K., Shimasaki N., Fukushima H., Hara M., Ogata T., and Matsuo N.2001. Female patient showing hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). Am. J. Hum. Genet. 69(3):664–665.
Ku C.L., Dupuis-Girod S., Dittrich A.M., Bustamante J., Santos O.F., Schulze I., Bertrand Y., Couly G., Bodemer C., Bossuyt X., Picard C., and Casanova J.L.2005. NEMO mutations in 2 unrelated boys with severe infections and conical teeth. Pediatrics. 115(5):e615–e619.
Ku C.L., Picard C., Erdos M., Jeurissen A., Bustamante J., Puel A., von Bernuth H., Filipe-Santos O., Chang H.H., Lawrence T., Raes M., Marodi L., Bossuyt X., and Casanova J.L.2007. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J. Med. Genet. 44(1):16–23.
Lee W.I., Torgerson T.R., Schumacher M.J., Yel L., Zhu Q., and Ochs H.D.2005. Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome. Blood. 105(5):1881–1890.
Lopez-Granados E., Keenan J.E., Kinney M.C., Leo H., Jain N., Ma C.A., Quinones R., Gelfand E.W., and Jain A.2008. A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency. Hum. Mutat. 29(6):861–868.
Mancini A.J., Lawley L.P., and Uzel G.2008. X-linked ectodermal dysplasia with immunodeficiency caused by NEMO mutation: Early recognition and diagnosis. Arch. Dermatol. 144(3):342–346.
Mansour S., Woffendin H., Mitton S., Jeffery I., Jakins T., Kenwrick S., and Murday V.A.2001. Incontinentia pigmenti in a surviving male is accompanied by hypohidrotic ectodermal dysplasia and recurrent infection. Am. J. Med. Genet. 99(2):172–177.
Martinez-Pomar N., Munoz-Saa I., Heine-Suner D., Martin A., Smahi A., and Matamoros N.2005. A new mutation in exon 7 of NEMO gene: Late skewed X-chromosome inactivation in an incontinentia pigmenti female patient with immunodeficiency. Hum. Genet. 118(3–4):458–465.
McDonald D.R., Mooster J.L., Reddy M., Bawle E., Secord E., and Geha R.S.2007. Heterozygous N-terminal deletion of IkappaBalpha results in functional nuclear factor kappaB haploinsufficiency, ectodermal dysplasia, and immune deficiency. J. Allergy Clin. Immunol. 120(4):900–907.
Mooster J.L., Cancrini C., Simonetti A., Rossi P., Di Matteo G., Romiti M.L., Di Cesare S., Notarangelo L., Geha R.S., and McDonald D.R.2010. Immune deficiency caused by impaired expression of nuclear factor-kappaB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of the NEMO gene. J. Allergy Clin. Immunol. 126(1):127–132.e7.
Mousallem T., Yang J., Urban T.J., Wang H., Adeli M., Parrott R.E., Roberts J.L., Goldstein D.B., Buckley R.H., and Zhong X.P.2014. A nonsense mutation in IKBKB causes combined immunodeficiency. Blood. 124(13):2046–2050.
Niehues T., Reichenbach J., Neubert J., Gudowius S., Puel A., Horneff G., Lainka E., Dirksen U., Schroten H., Doffinger R., Casanova J.L., and Wahn V.2004. Nuclear factor kappaB essential modulator-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia. J. Allergy Clin. Immunol. 114(6):1456–1462.
Nielsen C., Jakobsen M.A., Larsen M.J., Muller A.C., Hansen S., Lillevang S.T., Fisker N., and Barington T.2014. Immunodeficiency associated with a nonsense mutation of IKBKB. J. Clin. Immunol. 34(8):916–921.
Nishikomori R., Akutagawa H., Maruyama K., Nakata-Hizume M., Ohmori K., Mizuno K., Yachie A., Yasumi T., Kusunoki T., Heike T., and Nakahata T.2004. X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival. Blood. 103(12):4565–4572.
Ohnishi H., Miyata R., Suzuki T., Nose T., Kubota K., Kato Z., Kaneko H., and Kondo N.2012. A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome. J. Allergy Clin. Immunol. 129(2):578–580.
Orange J.S., Brodeur S.R., Jain A., Bonilla F.A., Schneider L.C., Kretschmer R., Nurko S., Rasmussen W.L., Kohler J.R., Gellis S.E., Ferguson B.M., Strominger J.L., Zonana J., Ramesh N., Ballas Z.K., and Geha R.S.2002. Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations. J. Clin. Invest. 109(11):1501–1509.
Orange J.S., Jain A., Ballas Z.K., Schneider L.C., Geha R.S., and Bonilla F.A. 2004 a. The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation. J. Allergy Clin. Immunol. 113(4):725–733.
Orange J.S., Levy O., Brodeur S.R., Krzewski K., Roy R.M., Niemela J.E., Fleisher T.A., Bonilla F.A., and Geha R.S. 2004 b. Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J. Allergy Clin. Immunol. 114(3):650–656.
Orange J.S., Levy O., and Geha R.S. 2005. Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation. Immunol. Rev. 203:21–37.
Orstavik K.H., Kristiansen M., Knudsen G.P., Storhaug K., Vege A., Eiklid K., Abrahamsen T.G., Smahi A., and Steen-Johnsen J. 2006. Novel splicing mutation in the NEMO (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome inactivation. Am. J. Med. Genet. A. 140(1):31–39.
Pannicke U., Baumann B., Fuchs S., Henneke P., Rensing-Ehl A., Rizzi M., Janda A., Hese K., Schlesier M., Holzmann K., Borte S., Laux C., Rump E.M., Rosenberg A., Zelinski T., Schrezenmeier H., Wirth T., Ehl S., Schroeder M.L., and Schwarz K. 2013. Deficiency of innate and acquired immunity caused by an IKBKB mutation. N. Engl. J. Med. 369(26):2504–2514.
Puel A., Reichenbach J., Bustamante J., Ku C.L., Feinberg J., Doffinger R., Bonnet M., Filipe-Santos O., de Beaucoudrey L., Durandy A., Horneff G., Novelli F., Wahn V., Smahi A., Israel A., Niehues T., and Casanova J.L. 2006. The NEMO mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation. Am. J. Hum. Genet. 78(4):691–701.
Roberts C.M., Angus J.E., Leach I.H., McDermott E.M., Walker D.A., and Ravenscroft J.C. 2010. A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency (OL-HED-ID). Eur. J. Pediatr. 169(11):1403–1407.
Salt B.H., Niemela J.E., Pandey R., Hanson E.P., Deering R.P., Quinones R., Jain A., Orange J.S., and Gelfand E.W. 2008. IKBKG (nuclear factor-kappa B essential modulator) mutation can be associated with opportunistic infection without impairing Toll-like receptor function. J. Allergy Clin. Immunol. 121(4):976–982.
Schimke L.F., Rieber N., Rylaarsdam S., Cabral-Marques O., Hubbard N., Puel A., Kallmann L., Sombke S.A., Notheis G., Schwarz H.P., Kammer B., Hokfelt T., Repp R., Picard C., Casanova J.L., Belohradsky B.H., Albert M.H., Ochs H.D., Renner E.D., and Torgerson T.R. 2013. A novel gain-of-function IKBA mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy. J. Clin. Immunol. 33(6):1088–1099.
Schweizer P., Kalhoff H., Horneff G., Wahn V., and Diekmann L. 1999. [Polysaccharide specific humoral immunodeficiency in ectodermal dysplasia. Case report of a boy with two affected brothers]. Klin. Padiatr. 211(6):459–461.
Vinolo E., Sebban H., Chaffotte A., Israel A., Courtois G., Veron M., and Agou F. 2006. A point mutation in NEMO associated with anhidrotic ectodermal dysplasia with immunodeficiency pathology results in destabilization of the oligomer and reduces lipopolysaccharide- and tumor necrosis factor-mediated NF-kappa B activation. J. Biol. Chem. 281(10):6334–6348.
von Bernuth H., Ku C.L., Rodriguez-Gallego C., Zhang S., Garty B.Z., Marodi L., Chapel H., Chrabieh M., Miller R.L., Picard C., Puel A., and Casanova J.L. 2006. A fast procedure for the detection of defects in Toll-like receptor signaling. Pediatrics. 118(6):2498–2503.
von Bernuth H., Puel A., Ku C.L., Yang K., Bustamante J., Chang H.H., Picard C., and Casanova J.L. 2005. Septicemia without sepsis: Inherited disorders of nuclear factor-kappa B-mediated inflammation. Clin. Infect. Dis. 41(Suppl 7):S436–S439.
Zonana J., Elder M.E., Schneider L.C., Orlow S.J., Moss C., Golabi M., Shapira S.K., Farndon P.A., Wara D.W., Emmal S.A., and Ferguson B.M. 2000. 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. 67(6):1555–1562.
Information & Authors
Information
Published In
LymphoSign Journal
Volume 3 • Number 4 • December 2016
Pages: 165 - 178
History
Received: 23 August 2016
Accepted: 10 November 2016
Accepted manuscript online: 14 November 2016
Copyright
© 2016.
Authors
Metrics & Citations
Metrics
Other Metrics
Citations
Cite As
ArnonBroides. 2016. A database for immunodeficiency due to mutations in nuclear factor kappa B pathway genes. LymphoSign Journal.
3(4): 165-178. https://doi.org/10.14785/lymphosign-2016-0009
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
There are no citations for this item
View Options
View options
Get Access
Login options
Check if you access through your login credentials or your institution to get full access on this article.
