Somatic mutations of the l12a gene in V-kappa(1) light chain deposition disease - Potential effects on aberrant protein conformation and deposition

Light chain deposition disease (LCDD) and light chain amyloidosis (AL) are disorders of monoclonal immunoglobulin deposition in which normally soluble serum precursors form insoluble deposits in tissues. A common feature in b oth is the clonal proliferation of B-cells that produce pathogenic light ch ains. However, the deposits in LCDD differ from those in AL in that they ar e ultrastructurally granular rather than fibrillar and do not bind Congo re d or colocalize with amyloid P component or apolipoprotein E. The reason(s) for their differences are unknown but are likely multifactorial and relate d to their protein conformation and their interaction with other molecules and tissue factors in the microenvironment. Knowledge of the primary struct ure of the light chains in LCDD is very limited. In the present study two n ew kappa(1) light chains from patients with LCDD are described and compared to seven other reported kappa-LCDD proteins. The N-terminal amino acid seq uences of light chain GLA extracted from the renal biopsy and light chain C HO from myocardial tissue were each identical to the respective light chain s isolated from the urines and to the V-region amino acid sequences transla ted from the cloned cDNAs obtained from bone marrow cells. The germline V-r egion sequences, determined from the genomic DNA in both and in MCM, a prev iously reported kappa(1) LCDD Light chain, were identical and related to th e L12a germline gene. The expressed Light chains in all three exhibit amino acid substitutions that arise from somatic mutation and result in increase d hydrophobicity with the potential for protein destabilization and disorde red conformation.