Identification of a novel substitution in the constant region of a gene coding for an amyloidogenic kappa(1) light chain

Current concepts regarding the association between immunoglobulin (Ig) ligh t chain structure and AL amyloidosis (AL) emphasize Ig variable region amin o acid substitutions because the majority of light chain amyloid fibrils th at have been sequenced contain amino termini of the variable region with on ly small amounts of the constant region. In this report, we describe a pati ent with rapidly progressive AL whose amyloid deposits contained primarily monoclonal kappa light chain constant region fragments. We sequenced and an alyzed this AL protein, determining that it was an O18-O8 kappa(1) variant and that the constant region possessed an unusual Ser --> Asn substitution at position 177. Using pre-mortem bone marrow cells, we cloned and sequence d the cDNA for this AL protein (HCAK1) and, using DNA from post-mortem soma tic tissue, we cloned and sequenced the patient's kappa germline O18-O8 don or and kappa constant region (C kappa) gene segments. The cDNA that coded f or HCAK1 contained a variable region that was derived from O18-O8, showing 96.1% homology to germline, and a C kappa that had a nucleotide substitutio n (AGC to AAC), resulting in the 177(Ser-Asn) replacement. Two C kappa gene s were cloned from somatic tissue DNA, one identical to a known C kappa seq uence and another containing this substitution which likely is a new C kapp a allotype. Our findings indicate that further investigation is warranted i nto the contributions genetic polymorphisms and light chain constant region s may make to amyloidogenesis. (C) 1999 Elsevier Science B.V. All rights re served.