An N-glycosylation hotspot in immunoglobulin κ light chains is associated with AL amyloidosis.

Abstract

Immunoglobulin light chain (AL) amyloidosis is caused by a small, minimally proliferating B-cell/plasma-cell clone secreting a patient-unique, aggregation-prone, toxic light chain (LC). The pathogenicity of LCs is encrypted in their sequence, yet molecular determinants of amyloidogenesis are poorly understood. Higher rates of N-glycosylation among clonal κ LCs from patients with AL amyloidosis compared to other monoclonal gammopathies indicate that this post-translational modification is associated with a higher risk of developing AL amyloidosis. Here, we exploited LC sequence information from previously published amyloidogenic and control clonal LCs and from a series of 220 patients with AL amyloidosis or multiple myeloma followed at our Institutions to define sequence and spatial features of N-glycosylation, combining bioinformatics, biochemical, proteomics, structural and genetic analyses. We found peculiar sequence and spatial pattern of N-glycosylation in amyloidogenic κ LCs, with most of the N-glycosylation sites laying in the framework region 3, particularly within the E strand, and consisting mainly of the NFT sequon, setting them apart with respect to non-amyloidogenic clonal LCs. Our data further support a potential role of N-glycosylation in determining the pathogenic behavior of a subset of amyloidogenic LCs and may help refine current N-glycosylation-based prognostic assessments for patients with monoclonal gammopathies.

• Authors: Alice Nevone, Maria Girelli, Silvia Mangiacavalli, Bruno Paiva, Paolo Milani, Pasquale Cascino, Maggie Piscitelli, Valentina Speranzini, Claudio Salvatore Cartia, Pietro Benvenuti, Ibai Goicoechea, Francesca Fazio, Marco Basset, Andrea Foli, Martina Nanci, Giulia Mazzini, Serena Caminito, Melania Antonietta Sesta, Simona Casarini, Paola Rognoni, Francesca Lavatelli, Maria Teresa Petrucci, Pier Paolo Olimpieri, Stefano Ricagno, Luca Arcaini, Giampaolo Merlini, Giovanni Palladini, Mario Nuvolone
• Journal: Leukemia (Leukemia) Vol. 36 Issue 8 Pg. 2076-2085 (08 2022) ISSN: 1476-5551 [Electronic] England
• PMID: 35610346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Immunoglobulin Light Chains
• Immunoglobulin kappa-Chains

Topics

• Amyloidosis (genetics)
• Glycosylation
• Humans
• Immunoglobulin Light Chains (genetics, metabolism)
• Immunoglobulin Light-chain Amyloidosis (genetics)
• Immunoglobulin kappa-Chains (genetics)
• Multiple Myeloma (genetics)