AN INSERTION DELETION EVENT IN MURINE IMMUNOGLOBULIN-KAPPA GENE RESEMBLES MUTATIONS AT HEAVY-CHAIN DISEASE LOCI

The analysis of spontaneous somatic mutants gives insights into the re gulation of gene expression. Human heavy-chain disease (HCD) is a mono clonal lymphoproliferative disorder characterized by the presence of t runcated immunoglobulin (Ig) heavy chains without associated light cha ins. To better understand the molecular mechanisms leading to the loss of light-chain production, we have examined a murine cell line model of heavy-chain disease. R15, a spontaneous mutant of the IgA, kappa-pr oducing myeloma cell line W3129, produces heavy chain but no light cha in. The variant DELTA15 derived from R15 resembles human HCD in that i t secretes a shortened heavy chain with no associated light chain. Clo ning and analysis of the R15 kappa light-chain gene revealed that a 35 8-nucleotide insertion of unknown origin replaced 22 bases of the wild -type leader-variable region (L-V) intron (IVS). Although this genomic change left the light-chain exons and known regulatory elements intac t, it altered the mRNA processing pathway, yielding two alternative RN A products, neither of which encodes a functional protein. This mutant therefore provides new insights into how genomic changes can influenc e gene expression.