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 regulation of gene expression. Human heavy-chain disease (HCD) is a monoclonal lymphoproliferative disorder characterized by the presence of truncated immunoglobulin (Ig) heavy chains without associated light chains. 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-producing myeloma cell line W3129, produces heavy chain but no light chain. The variant delta 15 derived from R15 resembles human HCD in that it secretes a shortened heavy chain with no associated light chain. Cloning and analysis of the R15 kappa light-chain gene revealed that a 358-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 intact, it altered the mRNA processing pathway, yielding two alternative RNA products, neither of which encodes a functional protein. This mutant therefore provides new insights into how genomic changes can influence gene expression.
Chou
C L
CL
Department of Microbiology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
Morrison
S L
SL
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015139:Blotting, Southern; D003001:Cloning, Molecular; D004247:DNA; D006362:Heavy Chain Disease / Q000235:genetics*; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D015183:Restriction Mapping; D014407:Tumor Cells, Cultured
D007145:Immunoglobulin kappa-Chains; D012333:RNA, Messenger; D004247:DNA