Kappa light chain-associated Fanconi's syndrome: molecular analysis of monoclonal immunoglobulin light chains from patients with and without intracellular crystals

Plasma cell dyscrasias may be responsible for Fanconi's syndrome, due to th e toxicity of a free monoclonal kappa light chain toward kidney proximal tu bules, Eight cases of Fanconi's syndrome were analyzed. We compared the str uctures of V kappa I. variability subgroup V domains from five cases of Fan coni's syndrome and one myeloma without renal involvement. Among Fanconi ca ses, four putative structures were obtained after molecular modeling by hom ology, and the other had previously been refined by X-ray crystallography, The complete sequences of one V kappa I, one V kappa III and N-terminal seq uences of two V kappa I light chains, from patients with different forms of Fanconi's syndrome, were compared with four previously studied sequences. All three kappa chains responsible for a 'classical' form with intralysosom al crystals and a low mass myeloma, were encoded by the LCO2/O12 germline g ene and had an unusual non-polar residue exposed to the solvent in the CDR- L1 loop, Of both V kappa I: light chains from patients with Fanconi's syndr ome without intracellular crystals, one derived from LCO2/O12 and the other from LCO8/O18 gene. Another feature that could be related to non-crystalli zation was the absence of accessible side chains in the CDR-L3 loop which i s known to be implicated in dimer formation.