title: Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK.
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.
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Hong-Ying
authors.initials: HY
authors.lastname: Wang
authors.forename: Chi A
authors.initials: CA
authors.lastname: Ma
authors.forename: Yongge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xiying
authors.initials: X
authors.lastname: Fan
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Pamela
authors.initials: P
authors.lastname: Edmonds
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.forename: Joao Bosco
authors.initials: JB
authors.lastname: Oliveira
authors.forename: Jordan
authors.initials: J
authors.lastname: Orange
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D000074049:Cytokine TWEAK; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology*
chemical_list: D053264:B-Cell Activating Factor; D000074049:Cytokine TWEAK; D052003:NF-kappa B p52 Subunit; C109743:TNFSF12 protein, human; C505719:TNFSF13B protein, human; D048069:Tumor Necrosis Factors