Germline Mutations in NFKB2 Implicate the Noncanonical NF-κB Pathway in the Pathogenesis of Common Variable Immunodeficiency
| Autor: | Wilfred Wu, Nancy H. Augustine, Harry R. Hill, Emily M. Coonrod, Karl V. Voelkerding, Guy A. Zimmerman, Zechariah F. Franks, Karin Chen, Adi V. Gundlapalli, Andrew S. Weyrich, Rebecca L. Margraf, Jacob D. Durtschi, Perry G. Ridge, Lynn B. Jorde, Attila Kumánovics, John F. Bohnsack, Nahla M. Heikal |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Heterozygote Adolescent Molecular Sequence Data Nonsense mutation Biology Article Cell Line Frameshift mutation Hypogammaglobulinemia Young Adult Germline mutation NF-kappa B p52 Subunit Antigen Genetics medicine Animals Humans Genetics(clinical) Amino Acid Sequence Genetic Testing Child Germ-Line Mutation Genetics (clinical) B-Lymphocytes Microscopy Confocal Common variable immunodeficiency medicine.disease Immunoglobulin A Pedigree Disease Models Animal Common Variable Immunodeficiency Phenotype Immunoglobulin M Immunoglobulin G Immunology Primary immunodeficiency biology.protein Female Signal Transduction |
| Zdroj: | The American Journal of Human Genetics. 93:812-824 |
| ISSN: | 0002-9297 |
| Popis: | 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-κB2 (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.2557CT (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-κB2 is the principal protein involved in the noncanonical NF-κB 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-κB signaling pathway as a genetic etiology for this primary immunodeficiency syndrome. |
| Databáze: | OpenAIRE |
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