Title | Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Wang H-Y, Ma CA, Zhao Y, Fan X, Zhou Q, Edmonds P, Uzel G, Oliveira JBosco, Orange J, Jain A |
Journal | Proc Natl Acad Sci U S A |
Volume | 110 |
Issue | 13 |
Pagination | 5127-32 |
Date Published | 2013 Mar 26 |
ISSN | 1091-6490 |
Keywords | Adult, Amino Acid Substitution, B-Cell Activating Factor, B-Lymphocytes, Cell Proliferation, Cell Survival, Child, Child, Preschool, Cytokine TWEAK, Down-Regulation, Female, Genetic Diseases, Inborn, Genetic Predisposition to Disease, Humans, Immunologic Deficiency Syndromes, Male, Mutation, Missense, NF-kappa B p52 Subunit, Tumor Necrosis Factors |
Abstract | Mutations in the TNF family of proteins have been associated with inherited forms of immune deficiency. Using an array-based sequencing assay, we identified an autosomal-dominant deficiency in TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) in a kindred with recurrent infection and impaired antibody responses to protein and polysaccharide vaccines. This mutation occurs in the sixth exon of TWEAK and results in the amino acid substitution R145C within the conserved TNF-homology domain of the full-length protein. TWEAK mutant protein formed high molecular weight aggregates under nonreducing conditions, suggesting an increased propensity for intermolecular interactions. As a result, mutant TWEAK associated with B-cell-activating factor (BAFF) protein and down-regulated the BAFF-mediated activation of the noncanonical NF-κB pathway through inhibition of p100 processing to p52, resulting in inhibition of BAFF-dependent B-cell survival and proliferation. As BAFF mediates T-cell-independent isotype switching and B-cell survival, our data implicate TWEAK as a disease-susceptibility gene for a humoral immunodeficiency. |
DOI | 10.1073/pnas.1221211110 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 23493554 |
PubMed Central ID | PMC3612633 |
Grant List | / / Intramural NIH HHS / United States |
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