Table 1.
Roles of NF-κB pathway in human diseases
| Protein name | Gene name | Type of disorder | Genetic mutations | Immunological defects in patients | Reference |
|---|---|---|---|---|---|
| NEMO | IKBKG | Incontinentia pigmenti (IP) |
c.184C>T (p.Arg62Ter) c.1219A>G (p.Met407Val) c.1259A>G (p.Ter420Trp) |
Failures of NF-κB induction in integument | 399 |
| EX4-10DEL | The IP-associated male lethality | 400 | |||
| NEMO | IKBKG | Hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) |
c.509T>C c.1167dupT |
Reduced memory B cells; failed to differentiate into plasma cells in response to CpG | 401 |
| c.1161dupC | Abnormally high levels of IgD and IgE | 402 | |||
|
c.1217A>T (p.Asp406Val) c.1249T>C (p.Cys417Arg) c.1250G>T (p.Cys417Phe) |
Suppression of IL-2 induction; impaired NF-κB activation; hyper-IgM syndrome; reduced memory B cells | 403–405 | |||
|
c.458T>G (p.Leu153Arg) c.1207C>T (p.Gln403Ter) |
Impaired NK cell cytotoxic activity | 406 | |||
| c.185G>A (p.Arg62Gln) | N/A | 407 | |||
| c.931G>A (p.Asp311Asn) | N/A | 408,409 | |||
| NEMO | IKBKG | Osteopetrosis and lymphedema- hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-HED-ID) | c.470A>C (p.Gln157Pro) | Hypogammaglobulinemia (IgG, IgM and IgA) and mixed T- and B-cell dysfunction | 410 |
| c.1182-1183delTT | Increased number of CD4 T cells and B cells with normal CD8 T cells; hyper-IgM syndrome | 411 | |||
| NEMO | IKBKG | Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) | c.863C>G (p.Ala288Gly) | Reduced TNF-α and LPS-induced NF-κB activation | 412 |
| c.768+5G>A | Impaired NF-κB activation as IκBα degradation | 413 | |||
| IVS4+866C>T | Impaired NF-κB activation as a generation of frameshift IκBα | 414 | |||
| 4.4-KB DUP | Reduced naïve-phenotype T cells and mitogen-induced proliferation of PBMC; increased levels of IgG and IgA; defect in LPS-induced NF-κB response | 415 | |||
| c.1167insC | Deficient cellular immunity | 416 | |||
| NEMO | IKBKG | Osteopetrosis and lymphedema-anhidrotic ectodermal dysplasia with immunodeficiency (OL-EDA-ID) | c.1259A>G (p.Ter420Trp) | Poor inflammatory reponse; impaired IL-1β, IL-18 and LPS-induced NF-κB activation | 399,417 |
| c.1238A>G (p.His413Arg) | Defect in LPS, IL-1β, and TNF-α-induced NF-κB activation; low NK and B memory cell counts | 418 | |||
| IκBα | NFKBIA | Anhidrotic ectodermal dysplasia With immunodeficiency (EDA-ID) |
c.96C>G (p.Ser32Arg) c.95G>A (p.Ser32Asn) |
Defective in memory T, B cells and Treg | 419 |
| c.107C>A (p.Ser36Tyr) | Reduced TLR/IL-1 and TNFR response to stimuli; reduction in γδ T and effector memory CD8 T cells | 420,421 | |||
| c.110T>G (p.Met37Arg) | Hyper-IgM syndrome with high/normal levels of IgM and low/absent levels of IgA, IgG and IgE; reduced memory B cells | 422 | |||
| c.110T>A (p.Met37Lys) | Decreased number of IL-17 producing T cells; impaired response to LPS and NF-κB activity | 423 | |||
| c.40G>T (p.Glu14Ter) | Defective in production of TNF-α and IL-12 of monocytes and IFN-γ of T cells | 424 | |||
| c.32G>A (p.Trp11Ter) | Impaired cytokine production in response to TLR ligands; | 425 | |||
| c.95G>T (p.Ser32Ile) | impaired response to TLR, IL-1β, IL-18 and TNFR; defective in memory T cells | 426 | |||
| p.Gln9Ter | Impaired response to LPS-induced NF-κB activity | 427 | |||
| IKKα | IKBKA | Severe fetal encasement malformation | c.1264C>T | Embryonic lethal | 428 |
| IKKβ | IKBKB | Severe combined immunodeficiency (SCID) | c.1292dup | Impaired immune response to stimulation; absent of regulatory T cells and γδ T cells | 429 |
| c.814C>T (p.Arg272Ter) | Hyper-IgM syndrome | 430 | |||
| c.607G>A (p.Val203Ile) | Immune dysregulation; deficiency of T and B cell | 431 | |||
| P105/50 | NFKB1 | Common variable immune deficiency (CVID) | c.730+4A>G | B cell dysfunction | 432 |
| c.491delG (p.G165A) | Hypogammaglobulinemia, decreased frequencies of class-switched B-cells and impaired T-cell proliferation | 433 | |||
| c.1149delT (p.Gly384Glu) | Hypogammaglobulinaemia with reduced B cells; excessive production of proinflammatory cytokines (IL-1β, TNF-α) | 434 | |||
| CYLD | CYLD | Familial cylindromatosis | c.547C>T | Familial Behcet-like autoinflammatory syndrome | 435 |
| c.1392dup (p.Gly465TrpfsX10) | Cell hyperproliferation | 436 | |||
| c.2252del | Cell hyperproliferation | 437 | |||
| CARD9 | CARD9 | Chronic mucocutaneous candidiasis | c.883C>T (p.Gln295Ter) | N/A | 438 |
| CARD9 | CARD9 | Deep dermatophytosis | c.865C>T (p.Gln289Ter) | Low numbers of Th17 cells | 439 |
|
c.184G>A c.288C>T |
N/A | 440 | |||
| CARD11 | CARD11 | B-cell expansion with NF-κB and T-cell anergy | c.368G>A (p.Gly123Asp) | Severe polyclonal B lymphocytosis | 441 |
| c.146G>A (p.Cys49Tyr) | Splenomegaly and profound polyclonal B-cell lymphocytosis; elevated transitional and mature naive B cells; few circulating class-switched/memory B cells | 442 | |||
|
p.Glu127Gly p.Gly116Ser |
Hereditary polyclonal B cell lymphocytosis | 443 | |||
| coiled-coil domain mutants | Diffuse large B cell lymphoma (DLBCL) | 444 | |||
| CARD11 | CARD11 | Immunodeficiency | deletion of exon 21 | Profound combined immunodeficiency | 445 |
| c.2833C>T (p.Gln945Ter) | Agammaglobulinemia; deficient T-cell function; normal T and B lymphocytes | 446 | |||
| c.2923C>T (p.Arg975Trp) p.Glu57Asp p.Leu194Pro | Low production of the cytokine IFN-γ | 447 | |||
| CARD14 | CARD14 | Psoriasis |
c.467T>C (p.Leu156Pro) c.349þ1G>A (p.Glu156del) c.412-414del |
N/A | 448 |
|
c.112C>T (p.Arg38Cys) c.424G>A (p.Glu142Lys) c.425A>G (p.Glu142Gly) c.511C>A (p.His171Asn) c.536G>A (p.Arg179His) c.571G>T (p.Val191Leu) c.599G>A (p.Ser200Asn) c.854A>G (p.Asp285Gly) c.1778T>A (p.Ile593Asn) c.349G>A (p.Gly117Ser) c.413A>C (p.Glu138Ala) |
Complex interplay between keratinocytes, skin resident immune cells and infiltrating leukocytes, including neutrophils, macrophages, conventional and plasmacytoid dendritic cells | 449–451 | |||
| MALT1 | MALT1 | Combined immunodeficiency (CID) | c.266G>T (p.Ser89Ile) | Normal numbers of T and B lymphocytes; impaired cellular and humoral immunity | 452 |
| c.1739G>C (p.Trp580Ser) | Severe dermatitis, severe inflammatory gastrointestinal disease and pneumonia | 453 | |||
| BCL10 | BCL10 | Combined immunodeficiency (CID) + autoimmunity | c.57+1G>A | Defects in both hematopoietic and non-hematopoietic immunity | 454 |
| BCL10 | BCL10 | Germ cell tumor and Non-Hodgkin’s Lymphoma |
c.499dup c.172C>G c.427-428dup |
MALT B Cell Lymphoma | 455,456 |
| A20 | TNFAIP3 | Behcet-like autoimmunity | c.547C>T | N/A | 457 |
|
c.680T>A c.671delT (p.Phe224Ser) c.811C>T c.1809delG (p.Thr604Arg) c.918C>G c.799delG (p.Pro268Leu) |
Increased egradation of IκBα and nuclear translocation of the p65 subunit; increased production of NF-κB-mediated proinflammatory cytokines | 458 | |||
| RIP1 | RIPK1 | Immunodeficiency |
c.4del c.21del c.2064del |
Immunodeficiency with lymphopenia | 459 |
| RIP1 | RIPK1 | Autoinflammatory Syndrome |
p.Asp324Asn p.Asp324His p.Asp324Tyr |
Severe intermittent lymphadenopathy | 460 |
| NIK | MAP3K14 | Combined immunodeficiency (CID) | c.1694C>G (p.Pro565Arg) | B-cell lymphopenia; decreased frequencies of class-switched memory B cells; hypogammaglobulinemia; impaired ICOSL expression | 461 |
| RelB | RELB | Combined immunodeficiency (CID) | c.1191C>A (p.Tyr397Ter) | Arrested B cells development; poor production of immunoglobulins; reduced output of thymus | 462 |
| p100/52 | NFKB2 | Common variable immune deficiency (CVID) |
c.2564delA (p.Lys855Ser) c.2557C>T |
Childhood-onset hypogammaglobulinemia; autoimmune features | 463 |
|
c.2556_2563del c.2594A>G (p.Asp865Gly) c.2600C>T (p.Ala867Val) c.2557C>T (p.Arg853Ter) |
Severe B-cell deficiency; immunodeficiencies; hypogammaglobulinemia | 464–466 | |||