Expression of the pre–B-cell receptor (pre-BCR) by pre-BII cells constitutes a crucial checkpoint in B-cell differentiation. Mutations that affect the pre–B-cell receptor result in early B-cell differentiation blockades that lead to primary B-cell immunodeficiencies. BLNK adaptor protein has a key role in the pre–B-cell receptor signaling cascade, as illustrated by the abnormal B-cell development in the 4 patients withBLNKgene defects reported to date. However, the BLNK protein's precise function in human B-cell differentiation has not been completely specified.Methods:
B-cell development, including IgVH and Vk chain repertoires analysis, was studied in the bone marrow of a new case of BLNK deficiencyin vitroandin vivo.Results:
Here, we report on a patient with agammaglobulinemia, with a total absence of circulating B cells. We detected a homozygous mutation inBLNK, which leads to the complete abrogation of BLNK protein expression. In the bone marrow, we identified a severe differentiation blockade at the pre–BI- to pre–BII-cell transition. IgVH gene rearrangements and selection of the IgH repertoire were normal, whereas the patient's pre-BI cells showed very restricted usage of the IgVκ repertoire. Complementation of bone marrow progenitors from the patient with theBLNKgene and transplantation into NOD/SCID/γcko mice allowed the complete restoration of B-cell differentiation and a normal usage of the IgVκ genes.