Light chain cardiomyopathy. Structural analysis of the light chain tissue deposits.
Cardiomyopathy due to monoclonal light chain deposits is a complication of plasma cell disorders. The deposits may be either fibrillar as in light chain amyloid or nonfibrillar as in light chain deposition disease. The reasons for these structural differences are still unknown. We characterized the myocardial deposits by immunohistochemical examination of sections and extraction and biochemical analysis of the tissue deposits in a patient (MCM) who died of myeloma and systemic light chain deposition disease. Amino acid sequence analysis of the extracted nonfibrillar MCM kappa-light chain reveals that it belongs to the L12a germline subset of the kappa(I) protein and contains five distinctive amino acid substitutions (three in the framework region III and two in the complementarity-determining region III) that have not been reported previously in the same positions in other kappa(I) light chains. The theoretically determined isoelectric point (pI 8.21) of the MCM light chain is high compared with the low isoelectric point of other Bence Jones proteins from subjects without light chain deposition disease. The diffuse binding to basement membranes and the high isoelectric point of the MCM kappa-light chain suggest electrostatic interaction as a possible mechanism of tissue deposition. The spatial locations of the five distinctive residues and a sixth rare substitution of the MCM protein modeled on the backbone structure of REI, a kappa(I)-soluble Bence Jones light chain of known three-dimensional structure, may be responsible for protein destabilization, partial unfolding, and aggregation leading to tissue deposition.
Gallo
G
G
Department of Pathology, New York University Medical Center, New York 10016, USA.
Goñi
F
F
Boctor
F
F
Vidal
R
R
Kumar
A
A
Stevens
F J
FJ
Frangione
B
B
Ghiso
J
J
D000328:Adult; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis*; D001536:Bence Jones Protein / Q000032:analysis / Q000737:chemistry / Q000302:isolation & purification; D009202:Cardiomyopathies / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D006801:Humans; D006942:Hypergammaglobulinemia / Q000150:complications / Q000276:immunology / Q000473:pathology; D007147:Immunoglobulin Light Chains / Q000032:analysis* / Q000737:chemistry* / Q000302:isolation & purification; D007145:Immunoglobulin kappa-Chains / Q000032:analysis / Q000302:isolation & purification / Q000502:physiology; D007150:Immunohistochemistry; D007526:Isoelectric Point; D008297:Male; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000150:complications / Q000276:immunology / Q000473:pathology; D009206:Myocardium / Q000737:chemistry* / Q000473:pathology* / Q000648:ultrastructure
D000596:Amino Acids; D007147:Immunoglobulin Light Chains; D007145:Immunoglobulin kappa-Chains; D001536:Bence Jones Protein