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Blood. 2014 Nov 6;124(19):2964-72. doi: 10.1182/blood-2014-06-578542. Epub 2014 Sep 18.

Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100.

Author information

1
Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Translational Research Unit, Canberra Hospital, Canberra, ACT, Australia;
2
Department of Immunology, Westmead Hospital, Westmead, NSW, Australia; and.
3
Australian Phenomics Facility, Australian National University, Canberra, ACT, Australia.
4
Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Australian Phenomics Facility, Australian National University, Canberra, ACT, Australia.

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.

PMID:
25237204
PMCID:
PMC4321335
DOI:
10.1182/blood-2014-06-578542
[Indexed for MEDLINE]
Free PMC Article

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