title: Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency.
abstract: 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.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-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.
authors.affiliation: Department of Pediatrics, Division of Allergy, Immunology & Rheumatology, University of Utah, Salt Lake City, UT 84108, USA. Electronic address: karin.chen@hsc.utah.edu.
authors.forename: Karin
authors.initials: K
authors.lastname: Chen
authors.forename: Emily M
authors.initials: EM
authors.lastname: Coonrod
authors.forename: Attila
authors.initials: A
authors.lastname: Kumánovics
authors.forename: Zechariah F
authors.initials: ZF
authors.lastname: Franks
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Durtschi
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Margraf
authors.forename: Wilfred
authors.initials: W
authors.lastname: Wu
authors.forename: Nahla M
authors.initials: NM
authors.lastname: Heikal
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Augustine
authors.forename: Perry G
authors.initials: PG
authors.lastname: Ridge
authors.forename: Harry R
authors.initials: HR
authors.lastname: Hill
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Jorde
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Weyrich
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
authors.forename: Adi V
authors.initials: AV
authors.lastname: Gundlapalli
authors.forename: John F
authors.initials: JF
authors.lastname: Bohnsack
authors.forename: Karl V
authors.initials: KV
authors.lastname: Voelkerding
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D002648:Child; D017074:Common Variable Immunodeficiency / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008297:Male; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D052003:NF-kappa B p52 Subunit / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; C498207:Nfkb2 protein, mouse