The X‐linked immunodeficiency defect in the mouse is corrected by expression of human Bruton's tyrosine kinase from a yeast artificial chromosome transgene

Abstract

Mutations in the gene for Bruton's tyrosine kinase result in the B cell differentiation defects X‐linked agammaglobulinemia in man and X‐linked immunodeficiency in mice. Here we describ the generation of two yeast artificial chromosome (YAC)‐transgenic mouse strains in which high‐level expression of human Btk is provided by endogenous regulatory cis‐acting elements that are present on a 340‐kb transgene, Yc340‐hBtk. The expression pattern of the transgenic human Btk was found to parallel that of the endogenous murine gene. When the Yc340‐hBtk‐transgenic mice were mated onto a Btk‐deficient background, the xid B cell defects were fully corrected: conventional and CD5⁺ B‐1 B cells were present in normal numbers, serum IgM and IgG3 levels as well as responses to T cell‐independent type II antigens were in the normal ranges. In vivo competition experiments in Btk^+/− female mice demonstrated that in the conventional B cell population the Yc340‐hBtk transgene could fully compensate the absence of expression of endogenous murine Btk. We conclude that in the YAC‐transgenic mice Btk is appropriately expressed in the context of native regulatory sequences.