Protein Engineering, Vol. 12, No. 4, 363-369,
April 1999
© 1999 Oxford University Press
Kappa light chain-associated Fanconi's syndrome: molecular analysis of monoclonal immunoglobulin light chains from patients with and without intracellular crystals
1 INSERM U25, Laboratoire d'Immunologie Clinique, Hôpital Necker, 161 rue de Sèvres, F-75015 Paris, 3 Laboratoire de Neuropharmacologie et Neurochimie, Université Claude Bernard, 8 Avenue Rockefeller, F-69373 Lyon, France, 4 NYU Medical Center, Department of Pathology, 550 First Avenue, New York, NY 10016, USA, 5 INSERM U489 and Renal Division, Hôpital Tenon, 4 rue de la Chine, F-75020 Paris, France, 6 Center for Mechanistic Biology and Biotechnology, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, IL 60439, USA
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 V
I 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 VI, one VIII and N-terminal sequences of two VI 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 VI 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.
Keywords: Bence–Jones protein/human/kidney/myeloma/protein structure
2 To whom correspondence should be addressed
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