Glycosylation of immunoglobulin light chains associated with amyloidosis

Abstract

AL amyloidosis is a fatal disease caused by deposition of immunoglobulin light chains in a fibrillarforin (AL) in various organs. By searching the Kabat database of immunoglobulin sequences using the KabatMan software, we have shown that there is a preponderance of the consensus glycosylation sequon (AsnXxxSer/Thr) in the framework regions of amyloid light chains. We have characterised by computer graphics simulations, NMR spectroscopy and carbohydrate biochemistry the structure and conformation of the oligosaccharide from amyloid protein AL MS (lamba1) and from the amyloid associated Bence Jones protein of patient MH (kappa1). These proteins have glycosylation in the hypervariable complementarity-determining region versus framework region, respectively. Both contained a 2-6 sialylated core fucosylated biantennary chain mostly with bisecting GIcNAc. Together our results suggest that light chain glycosylation may be one of several modifications which may render the protein more prone to amyloid formation.

Glycoproteomic analysis of abnormal N-glycosylation on the kappa chain of cryocrystalglobulin in a patient of multiple myeloma

“…Stevens et al 11,12) have reported that more than 80% of amyloidogenic κ1 variable domains are identifiable by the presence of substitutions acquiring a consensus Asn for N-glycosylation. Omtvedt et al 13) have also independently obtained the data suggesting that there is a preponderance of consensus glycosylation sequon in amyloidogenic light chains, to which sialylated and corefucosylated biantennary oligosaccharides mostly with bisecting GlcNAc were preferentially linked. Crystalglobulinemia has been thought to be a different syndrome from AL amyloidosis, however we found an interesting case of crystalglobulinemia, in which the κ chain was glycosylated, suggesting a common molecular mechanism underlying both AL amyloidosis and crystalglobulinemia.…”

Progesterone induces a switch in oligosaccharyltransferase isoform expression: Consequences on IgG N-glycosylation

“…In these cases, these antibodies may be beneficial or harmful to the host depending on the nature of the antigen (self or non-self) and the particular situation of their action [12,13]. Alternatively, carbohydrates in the variable regions may affect the biological activity [14] or stability [15] of immunoglobulins without altering their affinity for antigens. In line with these observations, it was demonstrated that follicular lymphoma cells produce IgG/IgM with an oligomannosetype oligosaccharide attached to the antigen binding site [16].…”

Nonsecretory multiple myeloma with amyloidosis. A case report and review of the literature

“…Amyloidosis is the end result of a dynamic process in which normally soluble proteins form insoluble fibrils [20]. Glenner et al demonstrated that amyloid fibrils in a patient with amyloidosis were identical to the variable segment of a monoclonal light chain.…”