Co-expression of full-length and truncated Ig mu-chains in human B lymphocytes results from alternative splicing of a single primary RNA transcript.

A survey of Ig synthesis among mu-heavy chain-producing human B cell lines indicated that roughly one-third co-express full length (mu+) and a particular type of truncated mu-chain (designated mu'). The relative molecular size of the intracellular form of this truncated mu-chain and its normal pattern of N-glycosylation suggested that mu'-chains were missing a single Ig domain at the protein level. Cell-free translation of polyA+ RNA from mu'-producing human B cell lines generated appropriate mu'-translation products, and Northern blot analysis demonstrated the presence of correspondingly truncated mu'-transcripts in these lines. These results pointed to a pretranslational basis for mu+/mu' co-expression. Sequencing of mu+- and mu'-cDNA clones from two human B cell lines showed that mu+- and mu'-transcripts derive from the same primary transcript, with mu'-mRNA formed by a direct leader-to-C mu 1 exon splice such that the heavy chain variable region exon is excluded via a cassette-type alternative splicing mechanism. Southern blot analysis of the rearranged Ig heavy chain genes in one B cell line confirmed that the co-expressed mu+- and mu'-mRNA derive from the same rearranged Ig heavy chain gene. mu'-cDNA clones were readily isolated from normal human bone marrow lymphocytes, whereas peripheral B cells do not appear to express mu'-transcripts. The frequent occurrence of mu'-mRNA in B cell lines, and its high relative expression in untransformed bone marrow lymphocytes attest to a mode of post-transcriptional control of Ig gene expression that may have implications for human B cell development.