B cell maturation antigen (BCMA) is a TNF superfamily protein expressed predominantly on plasmablasts and plasma cells. BCMA, along with TACI and BAFF-R, has been implicated for proper B cell maturation, differentiation, and survival. Patients with variants in TACI and BAFF-R have common variable immunodeficiency (CVID), but the impact of BCMA variants on human disease has not yet been reported. Here, we describe three patients from two consanguineous families who presented with early onset recurrent upper and lower respiratory tract infections. Immunological assessments of the patients demonstrated hypogammaglobulinemia, poor vaccine responses, and/or reduced isohemagglutinin titers, which were consistent with CVID. Whole-exome sequencing identified the same homozygous missense variant in TNFRSF17 (encoding BCMA), in three patients from two unrelated families. All known related family members who were heterozygous for the variant were unaffected. Overexpression of the patients’ BCMA variant in 293T cells revealed impaired protein stability and defective downstream signaling. Knockout of BCMA in naïve B cells from healthy controls resulted in impaired survival of in vitro–differentiated plasma cells. Together, our results indicate that BCMA is required for plasma cell survival in humans and that BCMA deficiency is a new genetic cause for CVID.
