LIGHT-CHAIN CARDIOMYOPATHY - STRUCTURAL-ANALYSIS OF THE LIGHT-CHAIN TISSUE DEPOSITS

Cardiomyopathy due to monoclonal light chain deposits is a complicatio n of plasma cell disorders. The deposits may be either fibrillar as in light chain amyloid or nonfibrillar as in light chain deposition dise ase. The reasons for these structural differences are still unknown. W e characterized the myocardial deposits by immunohistochemical examina tion analysis of the tissue deposits in a patient (MCM) who died of my eloma and systemic light chain deposition disease. Amino acid sequence analyses of the extracted nonfibrillar MCM kappa-light chain reveals that it belongs to the L12a germline subset of the kappa(1) protein an d contains five distinctive amino acid substitutions (three in the fra mework region III and two in the complementarity-determining region II I) that have not bee reported previously in the same positions in othe r kappa(1) light chains. The theoretically determined isoelectric poin t (pI 8.21) of the MCM light chain is high compared with the low isoel ectric point of other Bence Jones proteins from subjects without light chain deposition disease. The diffuse binding to basement membranes a nd the high isoelectric point of the MCM kappa-light chain suggest ele ctrostatic interaction as a possible mechanism of tissue deposition. T he spatial locations of the five distinctive residues and sixth rare s ubstitution of the MCM protein modeled on the backbone structure of RE I, a kappa(1)-soluble Bence Jones light chain of known three-dimension al structure, may be responsible for protein destabilization, partial unfolding, and aggregation leading to tissue deposition.