title: Fanconi's syndrome induced by a monoclonal Vkappa3 light chain in Waldenstrom's macroglobulinemia.
abstract: Fanconi's syndrome (FS) is a disorder of sodium-dependent proximal tubule reabsorption, which may complicate plasma cell disorders producing a free monoclonal light chain (LC). FS often occurs in the setting of smoldering myeloma and features cytoplasmic crystalline inclusions of monoclonal kappa LC in proximal tubular cells and malignant plasma cells. Although the clinical and pathological presentation may vary, including lack of crystal formation, monoclonal kappa LCs that underlie FS show a striking genetic and biochemical homogeneity: they almost always belong to the Vkappa1 subgroup of variability and originate from 2 germline genes, O2/O12 or O8/O18. Their variable domain sequences present unusual hydrophobic residues, responsible for the resistance to proteolysis, which leads to LC accumulation in the endocytic compartment of proximal tubule cells. We report a patient with slowly progressive Waldenstrom's macroglobulinemia and full-blown FS with accumulation of a monoclonal kappa LC within proximal tubules, but no detectable crystalline organization. This LC, which belonged to the unusual Vkappa3 subgroup and derived from the L2/L16 germline gene, showed no common substitution with previously described FS kappaI LC and was sensitive to trypsin digestion. These data show that molecular and biochemical characteristics of kappa LCs in patients with FS are more heterogeneous than initially suspected. Mechanisms other than resistance of LCs to endosomal proteolysis probably are involved in the pathogenesis of FS-associated plasma cell dyscrasias.
authors.affiliation: Department of Nephrology, University Hospital, Poitiers, France. f.bridoux@chu-poitiers.fr
authors.forename: Frank
authors.initials: F
authors.lastname: Bridoux
authors.forename: Christophe
authors.initials: C
authors.lastname: Sirac
authors.forename: Valérie
authors.initials: V
authors.lastname: Hugue
authors.forename: Catherine
authors.initials: C
authors.lastname: Decourt
authors.forename: Antoine
authors.initials: A
authors.lastname: Thierry
authors.forename: Nathalie
authors.initials: N
authors.lastname: Quellard
authors.forename: Ramzi
authors.initials: R
authors.lastname: Abou-Ayache
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Goujon
authors.forename: Michel
authors.initials: M
authors.lastname: Cogné
authors.forename: Guy
authors.initials: G
authors.lastname: Touchard
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology* / Q000652:urine; D001483:Base Sequence; D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology; D005198:Fanconi Syndrome / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D005803:Genes, Immunoglobulin; D018095:Germ-Line Mutation; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000276:immunology*; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000209:etiology; D007687:Kidney Tubules, Proximal / Q000276:immunology / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D014357:Trypsin / Q000378:metabolism; D008258:Waldenstrom Macroglobulinemia / Q000150:complications* / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D014357:Trypsin