X-linked agammaglobulinemia: new approaches to old questions based on the identification of the defective gene

Ornella Parolini, Mary Ellen Conley, Jurg Rohrer, Dario Campana

Research output: Contribution to journalArticle

61 Citations (Scopus)


The identification of a cytoplasmic tyrosine kinase, Btk, as the defective protein in human XLA and xid in the mouse, supports the hypothesis that both disorders are due to defects in B-cell activation or differentiation. Phenotypic analysis of B-lineage cells and studies on X-chromosome inactivation patterns in both mice and human patients suggest that mutations in Bth do not affect entry of stem cells into the B-lineage pathway but they do inhibit progression at multiple steps along that pathway. Although the exact function of Btk in signal transduction is not yet known, it is probable that studies which correlate specific mutations in different patients with alterations in Btk function will provide clues about critical sites in the molecule. Diagnosis and genetic counseling for families at risk of carrying the gene for XLA will be improved almost immediately by the identification of the responsible gene. Improvements in therapy may come more slowly. The possibility of curative gene therapy is attractive; however, there are several features of Btk that suggest that this will be a challenging undertaking. Overexpression or expression in inappropriate cell lineages may carry unacceptable risks. Mutant proteins may interfere with the function of wild-type proteins provided by gene therapy. However, it is likely that a better understanding of Btk function and regulation will benefit not only patients with XLA but also other patients with defects in B-cell function.
Original languageEnglish
Pages (from-to)5-21
Number of pages17
JournalImmunological Reviews
Publication statusPublished - 1994


  • Agammaglobulinemia
  • Animals
  • B-Lymphocytes
  • Genetic Counseling
  • Genetic Linkage
  • Humans
  • Lymphocyte Activation
  • Protein-Tyrosine Kinases
  • X Chromosome


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