期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：16
页码：9547-9551
DOI：10.1073/pnas.95.16.9547
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 VL plus up to {approx}60 residues of the constant domain (CL). 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 CL-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 CLs 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 VL to be markedly susceptible to enzymatic digestion, whereas the CL 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 VL/CL packing within the fibrils may account for the unusual composition of the amyloid deposits. Additionally, we posit that the previously unrecognized Asn177 substitution represents yet another C{kappa} allotype, provisionally designated Km4.
