Detalle Publicación

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

Autores: Nevone, A.; Girelli, M.; Mangiacavalli, S.; Paiva, Bruno; Milani, P.; Cascino, P.; Piscitelli, M.; Speranzini, V.; Cartia, C. S.; Benvenuti, P.; Goicoechea Oroz, Ibai; Fazio, F.; Basset, M.; Foli, A.; Nanci, M.; Mazzini, G.; Caminito, S.; Sesta, M. A.; Casarini, S.; Rognoni, P.; Lavatelli, F.; Petrucci, M. T.; Olimpieri, P. P.; Ricagno, S.; Arcaini, L.; Merlini, G.; Palladini, G. (Autor de correspondencia); Nuvolone, M. (Autor de correspondencia)
Título de la revista: LEUKEMIA
ISSN: 0887-6924
Volumen: 36
Número: 8
Páginas: 2076 - 2085
Fecha de publicación: 2022
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 kappa 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 kappa 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.