title: Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100.
abstract: Most genetic defects that arrest B-cell development in the bone marrow present early in life with agammaglobulinemia, whereas incomplete antibody deficiency is usually associated with circulating B cells. We report 3 related individuals with a novel form of severe B-cell deficiency associated with partial persistence of serum immunoglobulin arising from a missense mutation in NFKB2. Significantly, this point mutation results in a D865G substitution and causes a failure of p100 phosphorylation that blocks processing to p52. Severe B-cell deficiency affects mature and transitional cells, mimicking the action of rituximab. This phenotype appears to be due to disruption of canonical and noncanonical nuclear factor κB pathways by the mutant p100 molecule. These findings could be informative for therapeutics as well as immunodeficiency.
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Translational Research Unit, Canberra Hospital, Canberra, ACT, Australia;
authors.forename: Cindy Eunhee
authors.initials: CE
authors.lastname: Lee
authors.affiliation: Department of Immunology, Westmead Hospital, Westmead, NSW, Australia; and.
authors.forename: David A
authors.initials: DA
authors.lastname: Fulcher
authors.affiliation: Australian Phenomics Facility, Australian National University, Canberra, ACT, Australia.
authors.forename: Belinda
authors.initials: B
authors.lastname: Whittle
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Translational Research Unit, Canberra Hospital, Canberra, ACT, Australia;
authors.forename: Rochna
authors.initials: R
authors.lastname: Chand
authors.affiliation: Department of Immunology, Westmead Hospital, Westmead, NSW, Australia; and.
authors.forename: Nicole
authors.initials: N
authors.lastname: Fewings
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Australian Phenomics Facility, Australian National University, Canberra, ACT, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Field
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Australian Phenomics Facility, Australian National University, Canberra, ACT, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Andrews
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Australian Phenomics Facility, Australian National University, Canberra, ACT, Australia.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Translational Research Unit, Canberra Hospital, Canberra, ACT, Australia;
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
mesh_terms: D000328:Adult; D000505:Alopecia / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D057809:HEK293 Cells; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000276:immunology; D052003:NF-kappa B p52 Subunit / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010766:Phosphorylation / Q000276:immunology; D017354:Point Mutation; D017386:Sequence Homology, Amino Acid; D012720:Severity of Illness Index
chemical_list: D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human