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

Abstract

Light chain-associated amyloidosis is characterized by the deposition as fibrils of monoclonal light chain-related components consisting predominately of the variable domain (VL) or the VLplus up to ≈60 residues of the constant domain (CL). Here, we describe a patient (designated BIF) with light chain-associated amyloidosis and κ Bence Jones proteinuria in whom, notably, >80% of the amyloid deposits were comprised of CL-related material. The extracted amyloid protein consisted of 99 aa residues identical in sequence to the main portion of the Cκregion (positions 109–207) of the precursor Bence Jones protein. Remarkably, the CLs from both molecules contained a Ser→Asn substitution at position 177. This heretofore undescribed Cκalteration did not result from somatic mutation but rather was germline encoded. When tested in ourin vitrofibrillogenic kinetic assay, Bence Jones protein BIF was highly amyloidogenic. Notably, endopeptidase treatment of amyloid fibrils prepared from the native light chain revealed the VLto be markedly susceptible to enzymatic digestion, whereas the CLwas 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 VL/CLpacking within the fibrils may account for the unusual composition of the amyloid deposits. Additionally, we posit that the previously unrecognized Asn177substitution represents yet another Cκallotype, provisionally designatedKm4.