Light chain-associated amyloid deposits comprised of a novel κ constant domain

Light chain-associated amyloidosis is characterized by the deposition as fibrils of monoclonal light chain-related components consisting predominately of the variable domain (V-L) or the V-L plus up to approximate to 60 residues of the constant domain (C-L) Here, we describe a patient (designated BIF) with light chain-associated amyloidosis and kappa Bence Jones proteinuria in whom, notably, >80% of the amyloid deposits were comprised of C-L-related material. The extracted amyloid protein consisted of 99 aa residues identical in sequence to the main portion of the C-kappa region (positions 109-207) of the precursor Bence Jones protein. Remarkably, the C(L)s from both molecules contained a Ser-->Asn substitution at position 177, This heretofore undescribed C-kappa alteration did not result from somatic mutation but rather was germline encoded. When tested in our in vitro fibrillogenic kinetic assay, Bence Jones protein BIF was highly amyloidogenic, Notably, endopeptidase treatment of amyloid fibrils prepared from the native light chain revealed the V-L to be markedly susceptible to enzymatic digestion, whereas the C-L was protease-resistant, Our findings provide evidence that the fragmented light chains typically present in this disease result from proteolytic degradation and suggest that, in this case, conformational differences in V-L/C-L packing within the fibrils may account for the unusual composition of the amyloid deposits. Additionally, we posit that the previously unrecognized Asn(177) substitution represents yet another C-kappa, allotype, provisionally designated Km(4).