A 6-month-old boy presents with recurrent bacterial infections (Staphylococcus, Pneumococcus) and a profound absence of all peripheral blood B lymphocytes. Serum immunoglobulins of all isotypes are undetectable. T-cell numbers and function are normal. Genetic analysis reveals a hemizygous loss-of-function mutation in BTK. What is the most specific molecular mechanism by which BTK deficiency arrests B-cell development?

• A BTK is a cytoplasmic tyrosine kinase essential for pre-B-cell receptor (pre-BCR) signaling at the pro-B to pre-B transition; failure of BTK activation downstream of pre-BCR prevents phosphorylation of BLNK/SLP-65 and PLC-γ2, blocking B-cell development at the pro-B cell stage in the bone marrow ✓
• B BTK is required for T-cell help signaling; its absence prevents CD40L-CD40 interaction, blocking B-cell activation in germinal centers
• C BTK is required for RAG1/RAG2-mediated VDJ recombination of heavy chain genes; its absence causes failure of heavy chain rearrangement
• D BTK deficiency causes constitutional activation of PTEN, which suppresses PI3K-AKT and prevents B-cell survival signals from IL-7R

Explanation

X-linked agammaglobulinemia (Bruton's disease) is caused by mutations in BTK (Bruton tyrosine kinase) at Xq21.3. BTK is a downstream effector of the pre-BCR (mu heavy chain + surrogate light chain). When the pre-BCR is assembled and crosslinked, BTK is phosphorylated by Lyn/Syk, then activates PLC-γ2 (via BLNK/SLP-65 scaffolding), leading to Ca2+ mobilization, PKC and NF-κB activation, and transitional signals driving differentiation from large pre-B to small pre-B cells. Without BTK, this pre-BCR checkpoint signal fails completely, arresting development at the pro-B/large pre-B stage in the bone marrow, with no mature B cells in peripheral blood or secondary lymphoid organs.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.