BTK – Bruton-type agammaglobulinemia

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency characterized by a profound block in B-cell differentiation at the pre-B to B-cell transition and resultant panhypogammaglobulinemia. BTK encodes a 659-amino-acid cytoplasmic protein tyrosine kinase essential for B-cell receptor signaling. Disease-causing variants in BTK are distributed across the PH, TH, SH3, SH2, and kinase domains and result in absent circulating B cells and severe susceptibility to bacterial infections often presenting in infancy (PMID:8013627). XLA follows an X-linked recessive pattern, with hemizygous males manifesting disease and carrier females generally asymptomatic.

Genetic evidence for BTK involvement includes identification of over 600 unique variants in more than 600 unrelated male probands, encompassing missense, nonsense, frameshift, splice-site, and large deletion mutations. A nationwide Japanese study reported 51 patients from 35 families harboring diverse pathogenic BTK mutations, including recurrent and private alleles localized to two mutation hotspots in the PH and kinase domains (PMID:8695804). Truncating variants and canonical splice-site changes consistently result in loss of protein and severe phenotype.

Segregation analyses across multiple pedigrees confirm co-segregation of pathogenic variants with disease. For example, two affected brothers sharing the c.2T>C (p.Met1Thr) variant exhibit variable immunophenotypes yet both lack BTK activity (PMID:8644706). Carrier mothers display mosaic BTK expression in monocytes by flow cytometry, and obligate transmission of variants is documented in over 35 families (PMID:9427714).

Functional assays demonstrate that PH-domain mutations disrupt high-affinity binding to inositol 1,3,4,5-tetrakisphosphate, abolishing membrane localization (PMID:8939985, PMID:10196129). Structural modeling of eight kinase-domain mutations shows clustering on one face of the domain, each abrogating catalytic activity (PMID:7809124). Btk knockout mice recapitulate the human phenotype, with severe B-cell deficiency and impaired immunoglobulin production (PMID:7552994).

Phenotypic variability is observed with hypomorphic alleles; for instance, the p.Thr316Ala missense mutation preserves near-normal B-cell numbers but selectively impairs IgA responses (PMID:25589397). Such findings reflect modifier influences but do not refute the core BTK–XLA association.

In summary, germline BTK loss-of-function mutations cause XLA via haploinsufficiency and impaired BCR-mediated signaling. Comprehensive genetic testing, combined with flow cytometric BTK protein analysis, enables definitive diagnosis and carrier detection. Early identification facilitates immunoglobulin replacement therapy and informs prognosis.

References

• FEBS letters • 1994 • An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. PMID:8013627
• American journal of human genetics • 1996 • Discordant phenotype in siblings with X-linked agammaglobulinemia. PMID:8644706
• Blood • 1996 • Identification of Bruton's tyrosine kinase mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan. PMID:8695804
• Proceedings of the National Academy of Sciences of the United States of America • 1994 • Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease. PMID:7809124
• Immunity • 1995 • Defective B cell development and function in Btk-deficient mice. PMID:7552994
• The Journal of biological chemistry • 1996 • Mutation of the pleckstrin homology domain of Bruton's tyrosine kinase in immunodeficiency impaired inositol 1,3,4,5-tetrakisphosphate binding capacity. PMID:8939985
• International journal of hematology • 2015 • Mutations in Bruton's tyrosine kinase impair IgA responses. PMID:25589397

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