| First Author | Qin T | Year | 2020 |
| Journal | Front Immunol | Volume | 11 |
| Pages | 517544 | PubMed ID | 33658989 |
| Mgi Jnum | J:309163 | Mgi Id | MGI:6755945 |
| Doi | 10.3389/fimmu.2020.517544 | Citation | Qin T, et al. (2020) A Novel Homozygous Mutation Destabilizes IKKbeta and Leads to Human Combined Immunodeficiency. Front Immunol 11:517544 |
| abstractText | Mutations in the IKBKB gene cause severe immunodeficiency, characterized clinically by persistent respiratory or gastrointestinal infections. Targeted gene panel sequencing revealed a novel homozygous missense mutation in the IKBKB gene of a patient with immune dysregulation and combined T and B cell functional defects. PBMCs from the patient, Ikbkb Y397H mice, and transfected cells were used to elucidate how the Y395H mutation triggers IKKbeta deficiency and impairs immune function. Here, we found that cells from both the patient and Ikbkb Y397H mice lacked or showed decreased levels of IKKbeta protein, along with impaired lymphocyte function. IKKalpha and IKKgamma protein expression by human PBMCs harboring the Y395H mutation was normal, but degradation of IKKbeta protein was accelerated. Binding of human NF-kappaB to DNA in patient PBMCs fell upon stimulation with TNF-alpha or LPS. Additionally, a structural model of Y395H revealed loss of the hydrogen bond with D389. These data suggest that IKBKB deficiency induces abnormal IKKbeta protein degradation, leading to impaired NF-kappaB signaling and immune function. We postulate that the Y395H variant in the IKKbeta protein lost the hydrogen bond with D389, thereby affecting interaction between Y395 and D389 and increasing protein instability. |
