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

• DOI: 10.1038/s41375-022-01599-w
• Publication Date: 2022-05-24T06:05:20Z
• Authors: Alice Nevone; Maria Girelli; Silvia Mangiacavalli; Bruno Paiva; Paolo Milani; Pasquale Cascino; Maggie Piscitelli; Valentina Speranzini; Claudio Salvatore...; Pietro Benvenuti; Ibai Goicoechea; Francesca Fazio; Marco Basset; Andrea Foli; Martina Nanci; Giulia Mazzini; Serena Caminito; Melania Antoniett...; Simona Casarini; Paola Rognoni; Francesca Lavatelli; Maria Teresa Petr...; Pier Paolo Olimpieri; Stefano Ricagno; Luca Arcaini; Giampaolo Merlini; Giovanni Palladini; Mario Nuvolone
• Keywords: AL amyloidosis

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.