IDENTIFICATION AND CHARACTERIZATION OF A HUMAN V-LAMBDA-5 (T1) GERMLINE GENE THAT ENCODES STRUCTURALLY UNIQUE LAMBDA-LIGHT CHAINS

The human germline V-lambda repertoire consists of about 30 functional genes that have been classified into 10 families on the basis of homo logies in nucleotide sequences that encode approximately the first 96 to 104 residues of lambda light chains. One family, termed V(lambda)5 is of special interest because the lambda light chain products of thes e genes have unique structural features. We have now isolated from gen omic DNA one member of this family, designated IGLV5-1, using as a mol ecular probe a partial VlambdaS-germline-gene fragment generated by po lymerase chain reaction. IGLV5-1 contains all the requisite elements o f a potentially functional gene, including a V-lambda exon with an ope n reading frame specifying 104 residues. A VlambdaS-related cDNA (ZW) was also cloned from a bone marrow-derived plasma-cell population obta ined from a patient with light-chain-associated (AL) amyloidosis. Comp arison of the predicted protein sequences encoded by the IGLV5-1-germl ine gene, cDNA ZW, and three other reported V(lambda)5-related cDNAs w ith those of the deduced or expressed products of the other nine known human V-lambda-gene families revealed that V(lambda)5 proteins contai n distinctive primary structural features. These include the presence within the second complementarity determining region (CDR2) and the th ird framework region (FR3) of 11 and 34 amino acids, respectively, rat her than the 7 and 32 that occur in the most commonly expressed V(lamb da)1-, V(lambda)2- and V(lambda)3-type light chains. Although certain of the V-lambda-gene families encode either an elongated CDR2 or FR3, V(lambda)5 proteins are remarkable in that they have additional residu es in both regions of the molecule. In this respect, these polypeptide s are most similar to surrogate light-chain-associated human and mouse VpreB components that also have these unusual primary structural feat ures. Further, the four additional CDR2 residues and the two-residue F R3 insertion have been found among lambda-type light chains of certain non-mammalian species. The evolutionarily conserved nature of human V (lambda)5-related genes and, in particular, the presumably novel terti ary structural effects induced by the unique features of the lambda li ght chains encoded by these elements suggest that the V(lambda)5-gene family has biological and functional importance. (C) 1997 Elsevier Sci ence Ltd.