Secretion of a lambda 2 immunoglobulin chain is prevented by a single amino acid substitution in its variable region

We have studied two derivatives of the IgA (lambda 2) secreting myeloma cell line MOPC315:MOPC315.26, which produces and secretes a lambda 2 light chain, and MOPC315.37, which produces but does not secrete the lambda 2 chain. It has been reported that the only alteration in the MOPC315-37 lambda 2 chain is located in the variable region (Mosmann and Williamson, (1980) Cell 20, 283-292). In order to determine the nature of this alteration, we cloned the fragment of the chromosome containing the rearranged lambda 2 gene from both the nonsecreting variant MOPC315-37 and the normal lambda 2-secreting parent MOPC315-26 and determined their nucleotide sequence. We found that the nucleotide sequences coding for the leader peptide and for the constant region of the lambda 2 chain were identical in the secretor and nonsecretor. The sequences of the variable region differed at a single base pair corresponding to the first nucleotide in the codon for amino acid number 15. MOPC315-26 has a G in this position creating the codon GGT which codes for glycine, and MOPC315-37 has a C in this position creating the codon CGT which codes for arginine. Thus, we have demonstrated that a single amino acid substitution of a neutral amino acid, glycine, for a positively charged amino acid, arginine, results in the failure of a protein to be secreted.