SEQUENCES OF V-KAPPA-I SUBGROUP LIGHT-CHAINS IN FANCONIS-SYNDROME - LIGHT-CHAIN V-REGION GENE USAGE RESTRICTION AND PECULIARITIES IN MYELOMA-ASSOCIATED FANCONIS-SYNDROME

Certain monoclonal Ig light chains (LC) are responsible for marked dis turbances of proximal tubule cell functions (Fanconi's syndrome, FS). In patients with FS, intracellular crystal-like inclusions containing LC determinants are commonly found in plasma cells, macrophages, and r enal tubular cells. In an attempt at understanding the pathogenesis of myeloma-associated FS, we recently determined the first complete prim ary sequence of a kappa-LC (CHEB) responsible for the disease. We now report on the primary structure of three other kappa-LC of the V kappa I variability subgroup associated with FS (TRE, TRO, and DEL). After PCR amplification, cDNA encoding these LC were sequenced. CHEB, TRE, a nd TRO LC genes were found to be highly homologous to the same germlin e gene O2/O12. These patients had numerous intracellular crystals, whe reas the fourth patient, DEL, had no detectable crystals. The LC from the latter patient was homologous to another germline gene, O8/O18. Co mparison of these LC sequences to previously reported LC of the V kapp a I subgroup allowed identification of a number of unusual amino acid substitutions in the V region that had rarely or never been previously described at the corresponding positions. Some of these unusual subst itutions affect highly conserved amino acids located either in an exte rnal loop (residue 30) or in inner (residues 48 and 55) and outer (pos itions 63 and 72) beta-sheets that may be important for the structure and binding properties of the kappa-chains. These and several other su bstitutions, some of them shared with amyloidogenic kappa-LC, could in duce conformational alterations and represent a determinant pathogenic factor.