title: Kappa light chain-associated Fanconi's syndrome: molecular analysis of monoclonal immunoglobulin light chains from patients with and without intracellular crystals.
abstract: Plasma cell dyscrasias may be responsible for Fanconi's syndrome, due to the toxicity of a free monoclonal kappa light chain toward kidney proximal tubules. Eight cases of Fanconi's syndrome were analyzed. We compared the structures of VkappaI variability subgroup V domains from five cases of Fanconi's syndrome and one myeloma without renal involvement. Among Fanconi cases, four putative structures were obtained after molecular modeling by homology, and the other had previously been refined by X-ray crystallography. The complete sequences of one VkappaI, one VkappaIII and N-terminal sequences of two VkappaI 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 intralysosomal crystals and a low mass myeloma, were encoded by the LCO2/O12 germline gene and had an unusual non-polar residue exposed to the solvent in the CDR-L1 loop. Of both VkappaI light chains from patients with Fanconi's syndrome without intracellular crystals, one derived from LCO2/O12 and the other from LCO8/O18 gene. Another feature that could be related to non-crystallization was the absence of accessible side chains in the CDR-L3 loop which is known to be implicated in dimer formation.
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D002401:Cathepsin B / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005198:Fanconi Syndrome / Q000276:immunology*; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry*; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000494:pharmacology; D017421:Sequence Analysis; D017386:Sequence Homology, Amino Acid