Exome_sequencing_of_an_X_linked_B_cell_mutant

During the course of establishing a colony of mice carrying a knockout mutation in the Themis2 gene, we came across mice with low numbers of B cell in the blood, lymph nodes and spleen. Further analysis showed that the reduction in B cell numbers occurs already in the bone marrow, with a partial block in development at the pre-BCR checkpoint. This low B cell phenotype was found in mice both with and without the Themis2 mutation, and thus we believe it is not cause by the loss of Themis2. Inheritance analysis suggests that the mutation is X-linked and recessive. We initially only saw it in male pups from 2 separate breeders. Subsequent breeding of a mutant male with a sibling female who did not have the phenotype, generated female pups with the phenotype. The most obvious candidate for this phenotype on the X is the Btk gene. Mutations in Btk result in a small reduction in B cell numbers and strong impairment of B cell function. However sequence analysis of Btk cDNA shows no mutations in the mutant mice. Identification of the causative mutation is of interest because it may uncover a new gene or pathway controlling B cell development.