RESUMEN
Mutations in the gene encoding the protein tyrosine kinase Btk are associated with the human B cell immunodeficiency X-linked agammaglobulinemia (XLA). In the mouse, a point mutation in the Btk pleckstrin homology domain segregates with a milder X-linked immunodeficiency (xid). To assess the importance of Btk function in murine lymphopoiesis, we generated multiple embryonic stem cell clones bearing a targeted disruption of the btk gene and examined their potential to produce lymphocytes in both C57BL/6 and RAG2-/- host chimeric animals. These mice provide a complementary set of in vivo competition assays that formally establish the genetic basis for the xid phenotype. Although the null mutation yields a phenotype quite similar to that of xid, it also compromises expansion of B cell precursors. Our results suggest that the murine and human consequences of Btk deficiency differ only quantitatively, and represent the same disease process.
Asunto(s)
Linfocitos B/fisiología , Células Madre Hematopoyéticas/fisiología , Proteínas Tirosina Quinasas/deficiencia , Agammaglobulinemia Tirosina Quinasa , Agammaglobulinemia/genética , Animales , Secuencia de Bases , Quimera , Humanos , Recuento de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Datos de Secuencia Molecular , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/fisiología , Linfocitos T/fisiología , Cromosoma XRESUMEN
The cytoplasmic tyrosine kinase, Bruton's tyrosine kinase (Btk, formerly bpk or atk), is crucial for B cell development. Loss of kinase activity results in the human immunodeficiency, X-linked agammaglobulinemia, characterized by a failure to produce B cells. In the murine X-linked immunodeficiency (XID), B cells are present but respond abnormally to activating signals. The Btk gene, btk, was mapped to the xid region of the mouse X chromosome by interspecific backcross analysis. A single conserved residue within the amino terminal unique region of Btk was mutated in XID mice. This change in xid probably interferes with normal B cell signaling mediated by Btk protein interactions.