Gamma heavy chain disease in man: independent structural abnormalities and reduced transcription of a functionally rearranged lambda L-chain gene result in the absence of L-chains.

Human Ig heavy chain diseases of the alpha and gamma classes are characterized by the absence of light chain production as well as the disease-defining abnormalities in the heavy chain protein. Prior studies have suggested concomitant structural defects in productively rearranged L-chain genes as the reason for the absent L-chain proteins. We have found that the single rearranged lambda L-chain gene in the OMM heavy chain disease (HCD) cell line has a mutation in the splice donor site at the 3' end of the J exon, resulting in direct splicing of the 3' end of the leader to the acceptor site of the constant region. The cells contain an mRNA consisting of the leader-coding region joined directly to the constant region. The V-region exon is skipped and the shortened mRNA is translated into a truncated protein containing no V-region amino acids. We have also noted that, in contrast to most normal and neoplastic Ig-producing cells, the OMM cells produce an excess of heavy to light chain mRNA as well as protein. The excess is independent of the structural gene abnormality and is due to a low level of L-chain transcription, which can be increased by fusing the HCD cell to the murine myeloma cell line NS-1 or transfecting the defective OMM L-chain gene into a murine plasma cell. The latter data suggest that the OMM cells either lack a transcription factor present in mature plasma cells or have a functional repressor of L-chain transcription.