Impaired interleukin‐3 (IL‐3) response of the A/J mouse is caused by a branch point deletion in the IL‐3 receptor alpha subunit gene.

Interleukin‐3 (IL‐3) alone does not support hematopoietic colony formation of bone marrow cells from the A/J mouse. To elucidate the molecular lesion in A/J mice, we examined expression of the alpha and beta subunits of the IL‐3 receptor (IL‐3R). While IL‐3R beta was normally expressed, IL‐3R alpha was not detectable on the surface of A/J‐derived cells by antibody staining. Genetic linkage analysis using recombinant inbred mouse strains between A/J and IL‐3‐responsive C57BL/6 indicated that the IL‐3R alpha gene locus was responsible for the impaired IL‐3 response in A/J mice. Molecular cloning and characterization of A/J‐derived IL‐3R alpha cDNA revealed that it lacked the sequence corresponding to exon 8, which encodes 10 amino acid residues in the extracellular domain. The aberrant splicing was due to a 5 base pair deletion at the branch point in intron 7 and was reproduced in heterologous cells by transfecting with an IL‐3R alpha minigene carrying the deleterious intron. The A/J‐specific abnormal form of IL‐3R alpha was localized inside the cells, but not on the cell surface, providing the molecular basis for the impaired IL‐3 response in the A/J mouse.