title: The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes.
abstract: Both innate and adaptive immune responses are dependent on activation of nuclear factor kappaB (NF-kappaB), induced upon binding of pathogen-associated molecular patterns to Toll-like receptors (TLRs). In murine models, defects in NF-kappaB pathway are often lethal and viable knockout mice have severe immune defects. Similarly, defects in the human NF-kappaB pathway described to date lead to severe clinical disease. Here, we describe a patient with a hyper immunoglobulin M-like immunodeficiency syndrome and ectodermal dysplasia. Monocytes did not produce interleukin 12p40 upon stimulation with various TLR stimuli and nuclear translocation of NF-kappaB was impaired. T cell receptor-mediated proliferation was also impaired. A heterozygous mutation was found at serine 32 in IkappaBalpha. Interestingly, his father has the same mutation but displays complex mosaicism. He does not display features of ectodermal dysplasia and did not suffer from serious infections with the exception of a relapsing Salmonella typhimurium infection. His monocyte function was impaired, whereas T cell function was relatively normal. Consistent with this, his T cells almost exclusively displayed the wild-type allele, whereas both alleles were present in his monocytes. We propose that the T and B cell compartment of the mosaic father arose as a result of selection of wild-type cells and that this underlies the widely different clinical phenotype.
authors.affiliation: Dept. of Infectious Diseases, C5-P Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, Netherlands. C.M.Janssen@lumc.nl
authors.forename: Riny
authors.initials: R
authors.lastname: Janssen
authors.forename: Annelies
authors.initials: A
authors.lastname: van Wengen
authors.forename: Marieke A
authors.initials: MA
authors.lastname: Hoeve
authors.forename: Monique
authors.initials: M
authors.lastname: ten Dam
authors.forename: Miriam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Jacques
authors.initials: J
authors.lastname: van Dongen
authors.forename: Esther
authors.initials: E
authors.lastname: van de Vosse
authors.forename: Maarten
authors.initials: M
authors.lastname: van Tol
authors.forename: Robbert
authors.initials: R
authors.lastname: Bredius
authors.forename: Tom H
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: Corry
authors.initials: C
authors.lastname: Weemaes
authors.forename: Jaap T
authors.initials: JT
authors.lastname: van Dissel
authors.forename: Arjan
authors.initials: A
authors.lastname: Lankester
mesh_terms: D021581:Active Transport, Cell Nucleus; D000328:Adult; D000483:Alleles; D001402:B-Lymphocytes / Q000166:cytology; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002675:Child, Preschool; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000473:pathology; D005192:Family Health; D005220:Fathers; D005260:Female; D006579:Heterozygote; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D007075:Immunoglobulin M / Q000172:deficiency / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D009000:Monocytes / Q000378:metabolism; D009035:Mothers; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D010100:Oxygen / Q000378:metabolism; D016133:Polymerase Chain Reaction; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016897:Respiratory Burst; D012694:Serine / Q000737:chemistry; D013577:Syndrome; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D020672:I-kappa B Proteins; D007075:Immunoglobulin M; D053762:Interleukin-12 Subunit p40; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D021122:Protein Subunits; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D018664:Interleukin-12; D012694:Serine; D007371:Interferon-gamma; D004247:DNA; D010100:Oxygen