An N-glycosylation hotspot in immunoglobulin κ light chains is associated with AL amyloidosis.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
23
02
2022
accepted:
11
05
2022
revised:
05
05
2022
pubmed:
25
5
2022
medline:
4
8
2022
entrez:
24
5
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35610346
doi: 10.1038/s41375-022-01599-w
pii: 10.1038/s41375-022-01599-w
doi:
Substances chimiques
Immunoglobulin Light Chains
0
Immunoglobulin kappa-Chains
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2076-2085Subventions
Organisme : Cancer Research UK
ID : C355/A26819
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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