Identification and characterization of a human Vlambda5 (T1) germline gene that encodes structurally unique lambda light chains.

The human germline Vlambda repertoire consists of about 30 functional genes that have been classified into 10 families on the basis of homologies in nucleotide sequences that encode approximately the first 96 to 104 residues of lambda light chains. One family, termed Vlambda5, is of special interest because the lambda light chain products of these genes have unique structural features. We have now isolated from genomic DNA one member of this family, designated IGLV5-1, using as a molecular probe a partial Vlambda5-germline-gene fragment generated by polymerase chain reaction. IGLV5-1 contains all the requisite elements of a potentially functional gene, including a Vlambda exon with an open reading frame specifying 104 residues. A Vlambda5-related cDNA (ZW) was also cloned from a bone marrow-derived plasma-cell population obtained from a patient with light-chain-associated (AL) amyloidosis. Comparison of the predicted protein sequences encoded by the IGLV5-1-germline gene, cDNA ZW, and three other reported Vlambda5-related cDNAs with those of the deduced or expressed products of the other nine known human Vlambda-gene families revealed that Vlambda5 proteins contain distinctive primary structural features. These include the presence within the second complementarity determining region (CDR2) and the third framework region (FR3) of 11 and 34 amino acids, respectively, rather than the 7 and 32 that occur in the most commonly expressed Vlambda1-, Vlambda2- and Vlambda3-type light chains. Although certain of the Vlambda-gene families encode either an elongated CDR2 or FR3, Vlambda5 proteins are remarkable in that they have additional residues in both regions of the molecule. In this respect, these polypeptides are most similar to surrogate light-chain-associated human and mouse VpreB components that also have these unusual primary structural features. Further, the four additional CDR2 residues and the two-residue FR3 insertion have been found among lambda-type light chains of certain non-mammalian species. The evolutionarily conserved nature of human Vlambda5-related genes and, in particular, the presumably novel tertiary structural effects induced by the unique features of the lambda light chains encoded by these elements suggest that the Vlambda5-gene family has biological and functional importance.