Inherited Human BCL10 Deficiencies

Abstract

Human BCL10 deficiency causes combined immunodeficiency with bone marrow transplantation as its only curative option. To date, there are four homozygous mutations described in the literature that were identified in four unrelated patients. Here, we describe a fifth patient with a novel mutation and summarize what we have learned about BCL10 deficiency. Due to the severity of the disease, accurate knowledge of its clinical and immunological characteristics is instrumental for early diagnosis and adequate clinical management of the patients.

Keywords: BCL10; Primary immunodeficiency; combined immunodeficiency; inborn errors of immunity.

Figure 1.. Human BCL10 protein and mutations responsible of BCL10 deficiency

Schematic representation of human BCL10 with its two domains and germline mutations known to cause BCL10 deficiency indicated. CARD: caspase recruitment domain; S/T rich: serine/threonine rich region.

Figure 2.. A patient with CID and the novel BCL10 mutation: R42H

(A) Familial segregation of the BCL10 mutation R42H. (B) Sanger sequencing results for the region encompassing the mutation for the patient (P5), the patient’s father (I1), and the patient’s mother (I2). (C) Immunoblot analysis of BCL10 protein in BCL10^−/−’s SV40-fibroblasts transfected with 2 μg of WT BCL10 plasmid (WT), empty vector (mock), BCL10 R42H plasmid (R42H), BCL10^−/− SV40-fibroblasts electroporated (E) or BCL10^−/− SV40-fibroblasts non-electroporated (NE). GAPDH was used as a loading control and to normalize the quantification of BCL10. The panels illustrate the results from a single experiment, representative of three. (D and E) Production of IL-6 and IL-8, respectively, as assessed by ELISA, in BCL10^−/− SV40 fibroblasts non-transfected (BCL10^−/−), BCL10^−/− SV40 fibroblasts transfected with 2 μg of WT BCL10 plasmid (WT), or R42H BCL10 plasmid (R42H) after stimulation 24 h post-transfection with poly(I:C), LPS, Zymosan, and Curdlan. Mean values ± SD were calculated from 3 independent experiments. Non-significant (ns), p < 0.05 (*), 0.005(**), <0.005-0.0001 (***), 0.0001 (****) for different stimuli between BCL10^−/− and WT or BCL10^−/− R42H.