| First Author | Chen K | Year | 2013 |
| Journal | Am J Hum Genet | Volume | 93 |
| Issue | 5 | Pages | 812-24 |
| PubMed ID | 24140114 | Mgi Jnum | J:206674 |
| Mgi Id | MGI:5551676 | Doi | 10.1016/j.ajhg.2013.09.009 |
| Citation | Chen K, et al. (2013) Germline mutations in NFKB2 implicate the noncanonical NF-kappaB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet 93(5):812-24 |
| abstractText | Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by antibody deficiency, poor humoral response to antigens, and recurrent infections. To investigate the molecular cause of CVID, we carried out exome sequence analysis of a family diagnosed with CVID and identified a heterozygous frameshift mutation, c.2564delA (p.Lys855Serfs( *)7), in NFKB2 affecting the C terminus of NF-kappaB2 (also known as p100/p52 or p100/p49). Subsequent screening of NFKB2 in 33 unrelated CVID-affected individuals uncovered a second heterozygous nonsense mutation, c.2557C>T (p.Arg853( *)), in one simplex case. Affected individuals in both families presented with an unusual combination of childhood-onset hypogammaglobulinemia with recurrent infections, autoimmune features, and adrenal insufficiency. NF-kappaB2 is the principal protein involved in the noncanonical NF-kappaB pathway, is evolutionarily conserved, and functions in peripheral lymphoid organ development, B cell development, and antibody production. In addition, Nfkb2 mouse models demonstrate a CVID-like phenotype with hypogammaglobulinemia and poor humoral response to antigens. Immunoblot analysis and immunofluorescence microscopy of transformed B cells from affected individuals show that the NFKB2 mutations affect phosphorylation and proteasomal processing of p100 and, ultimately, p52 nuclear translocation. These findings describe germline mutations in NFKB2 and establish the noncanonical NF-kappaB signaling pathway as a genetic etiology for this primary immunodeficiency syndrome. |
