The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes.
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.
Janssen
Riny
R
Dept. of Infectious Diseases, C5-P Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, Netherlands. C.M.Janssen@lumc.nl
van Wengen
Annelies
A
Hoeve
Marieke A
MA
ten Dam
Monique
M
van der Burg
Miriam
M
van Dongen
Jacques
J
van de Vosse
Esther
E
van Tol
Maarten
M
Bredius
Robbert
R
Ottenhoff
Tom H
TH
Weemaes
Corry
C
van Dissel
Jaap T
JT
Lankester
Arjan
A
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
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