The X-linked immunodeficiency defect in the mouse is corrected by expression of human Bruton's tyrosine kinase from a yeast artificial chromosome transgene.
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 describe 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.
Maas
A
A
Department of Cell Biology and Genetics, Faculty of Medicine, Erasmus University Rotterdam, The Netherlands.
Dingjan
G M
GM
Savelkoul
H F
HF
Kinnon
C
C
Grosveld
F
F
Hendriks
R W
RW
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000917:Antibody Formation; D000955:Antigens, T-Independent / Q000276:immunology; D001402:B-Lymphocytes / Q000502:physiology*; D018244:Chromosomes, Artificial, Yeast; D005260:Female; D005816:Genetic Complementation Test; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology* / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*
D000955:Antigens, T-Independent; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse