Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

MULTIPLE MYELOMA, GAMMOPATHIES

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

Leukemia volume 36, pages 2076–2085 (2022)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Sequence and spatial features of predicted N-glycosylation of amyloidogenic and non-amyloidogenic clonal κ light chains.
Fig. 2: Biochemical and proteomics confirmation of N-glycosylation prediction in amyloidogenic κ light chains.
Fig. 3: Genomic versus somatic origin of the predicted N-glycosylation site in amyloidogenic κ light chains.
Fig. 4: Secondary structure analysis and structural mapping of N-glycosylation sites in amyloidogenic κ light chains.
Fig. 5: Prognostic significance of N-glycosylation site mapping within clonal κ light chains.

Similar content being viewed by others

Data availability

The data generated in this study are available within the article and its Supplementary Data Files. LC sequences have been deposited to GenBank (MZ595009-MZ595094, OM885091-OM885224).

References

  1. Merlini G, Dispenzieri A, Sanchorawala V, Schonland SO, Palladini G, Hawkins PN, et al. Systemic immunoglobulin light chain amyloidosis. Nat Rev Dis Prim. 2018;4:38.

    Article  PubMed  Google Scholar 

  2. Comenzo RL, Zhang Y, Martinez C, Osman K, Herrera GA. The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell burden. Blood. 2001;98:714–20.

    Article  CAS  PubMed  Google Scholar 

  3. Abraham RS, Geyer SM, Price-Troska TL, Allmer C, Kyle RA, Gertz MA, et al. Immunoglobulin light chain variable (V) region genes influence clinical presentation and outcome in light chain-associated amyloidosis (AL). Blood. 2003;101:3801–8.

    Article  CAS  PubMed  Google Scholar 

  4. Perfetti V, Casarini S, Palladini G, Vignarelli MC, Klersy C, Diegoli M, et al. Analysis of V(lambda)-J(lambda) expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r (lambdaIII) as a new amyloid-associated germline gene segment. Blood. 2002;100:948–53.

    Article  CAS  PubMed  Google Scholar 

  5. Prokaeva T, Spencer B, Kaut M, Ozonoff A, Doros G, Connors LH, et al. Soft tissue, joint, and bone manifestations of AL amyloidosis: clinical presentation, molecular features, and survival. Arthritis Rheum. 2007;56:3858–68.

    Article  PubMed  Google Scholar 

  6. Perfetti V, Palladini G, Casarini S, Navazza V, Rognoni P, Obici L, et al. The repertoire of lambda light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44. Blood. 2012;119:144–50.

    Article  CAS  PubMed  Google Scholar 

  7. Bodi K, Prokaeva T, Spencer B, Eberhard M, Connors LH, Seldin DC. AL-Base: a visual platform analysis tool for the study of amyloidogenic immunoglobulin light chain sequences. Amyloid. 2009;16:1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dwulet FE, O’Connor TP, Benson MD. Polymorphism in a kappa I primary (AL) amyloid protein (BAN). Mol Immunol. 1986;23:73–8.

    Article  CAS  PubMed  Google Scholar 

  9. Stevens FJ. Four structural risk factors identify most fibril-forming kappa light chains. Amyloid. 2000;7:200–11.

    Article  CAS  PubMed  Google Scholar 

  10. Omtvedt LA, Bailey D, Renouf DV, Davies MJ, Paramonov NA, Haavik S, et al. Glycosylation of immunoglobulin light chains associated with amyloidosis. Amyloid. 2000;7:227–44.

    Article  CAS  PubMed  Google Scholar 

  11. Karimi M, Sletten K, Westermark P. Biclonal systemic AL-amyloidosis with one glycosylated and one nonglycosylated AL-protein. Scand J Immunol. 2003;57:319–23.

    Article  CAS  PubMed  Google Scholar 

  12. Myran T, Husby G, Kyle RA, Sletten K. The amino acid sequence of a glycosylated AL-chain from a patient with primary amyloidosis. Amyloid. 2004;11:109–12.

    Article  CAS  PubMed  Google Scholar 

  13. Connors LH, Jiang Y, Budnik M, Theberge R, Prokaeva T, Bodi KL, et al. Heterogeneity in primary structure, post-translational modifications, and germline gene usage of nine full-length amyloidogenic kappa1 immunoglobulin light chains. Biochemistry. 2007;46:14259–71.

    Article  CAS  PubMed  Google Scholar 

  14. Kumar S, Murray D, Dasari S, Milani P, Barnidge D, Madden B, et al. Assay to rapidly screen for immunoglobulin light chain glycosylation: a potential path to earlier AL diagnosis for a subset of patients. Leukemia. 2019;33:254–7.

    Article  CAS  PubMed  Google Scholar 

  15. Dispenzieri A, Larson DR, Rajkumar SV, Kyle RA, Kumar SK, Kourelis T, et al. N-glycosylation of monoclonal light chains on routine MASS-FIX testing is a risk factor for MGUS progression. Leukemia. 2020;34:2749–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mellors PW, Dasari S, Kohlhagen MC, Kourelis T, Go RS, Muchtar E, et al. MASS-FIX for the detection of monoclonal proteins and light chain N-glycosylation in routine clinical practice: a cross-sectional study of 6315 patients. Blood Cancer J. 2021;11:50.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Milani P, Murray DL, Barnidge DR, Kohlhagen MC, Mills JR, Merlini G, et al. The utility of MASS-FIX to detect and monitor monoclonal proteins in the clinic. Am J Hematol. 2017;92:772–9.

    Article  CAS  PubMed  Google Scholar 

  18. Kourelis T, Murray DL, Dasari S, Kumar S, Barnidge D, Madden B, et al. MASS-FIX may allow identification of patients at risk for light chain amyloidosis before the onset of symptoms. Am J Hematol. 2018;93:E368–70.

    Article  PubMed  Google Scholar 

  19. Alameda D, Goicoechea I, Vicari M, Arriazu E, Nevone A, Rodriguez S, et al. Tumor cells in light-chain amyloidosis and myeloma show distinct transcriptional rewiring of normal plasma cell development. Blood. 2021;138:1583–9.

    Article  CAS  PubMed  Google Scholar 

  20. Gupta R, Brunak S. Prediction of glycosylation across the human proteome and the correlation to protein function. Pac Symp Biocomput. 2002;7:310–22.

  21. Lavatelli F, Mazzini G, Ricagno S, Iavarone F, Rognoni P, Milani P, et al. Mass spectrometry characterization of light chain fragmentation sites in cardiac AL amyloidosis: insights into the timing of proteolysis. J Biol Chem. 2020;295:16572–84.

    Article  CAS  PubMed  Google Scholar 

  22. van de Bovenkamp FS, Derksen NIL, Ooijevaar-de Heer P, van Schie KA, Kruithof S, Berkowska MA, et al. Adaptive antibody diversification through N-linked glycosylation of the immunoglobulin variable region. Proc Natl Acad Sci USA. 2018;115:1901–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Chicco D, Jurman G. The advantages of the Matthews correlation coefficient (MCC) over F1 score and accuracy in binary classification evaluation. BMC Genom. 2020;21:6.

    Article  Google Scholar 

  24. Imperiali B, Hendrickson TL. Asparagine-linked glycosylation: specificity and function of oligosaccharyl transferase. Bioorg Med Chem. 1995;3:1565–78.

    Article  CAS  PubMed  Google Scholar 

  25. Maley F, Trimble RB, Tarentino AL, Plummer TH Jr. Characterization of glycoproteins and their associated oligosaccharides through the use of endoglycosidases. Anal Biochem. 1989;180:195–204.

    Article  CAS  PubMed  Google Scholar 

  26. Palmisano G, Melo-Braga MN, Engholm-Keller K, Parker BL, Larsen MR. Chemical deamidation: a common pitfall in large-scale N-linked glycoproteomic mass spectrometry-based analyses. J Proteome Res. 2012;11:1949–57.

    Article  CAS  PubMed  Google Scholar 

  27. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hernandez RD, Uricchio LH, Hartman K, Ye C, Dahl A, Zaitlen N. Ultrarare variants drive substantial cis heritability of human gene expression. Nat Genet. 2019;51:1349–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Roussel A, Spinelli S, Deret S, Navaza J, Aucouturier P, Cambillau C. The structure of an entire noncovalent immunoglobulin kappa light-chain dimer (Bence-Jones protein) reveals a weak and unusual constant domains association. Eur J Biochem. 1999;260:192–9.

    Article  CAS  PubMed  Google Scholar 

  30. Ohtsubo K, Marth JD. Glycosylation in cellular mechanisms of health and disease. Cell. 2006;126:855–67.

    Article  CAS  PubMed  Google Scholar 

  31. Helenius A, Aebi M. Intracellular functions of N-linked glycans. Science. 2001;291:2364–9.

    Article  CAS  PubMed  Google Scholar 

  32. Gudelj I, Lauc G, Pezer M. Immunoglobulin G glycosylation in aging and diseases. Cell Immunol. 2018;333:65–79.

    Article  CAS  PubMed  Google Scholar 

  33. Quast I, Keller CW, Maurer MA, Giddens JP, Tackenberg B, Wang LX, et al. Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity. J Clin Investig. 2015;125:4160–70.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Arnold JN, Wormald MR, Sim RB, Rudd PM, Dwek RA. The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu Rev Immunol. 2007;25:21–50.

    Article  CAS  PubMed  Google Scholar 

  35. Dunn-Walters D, Boursier L, Spencer J. Effect of somatic hypermutation on potential N-glycosylation sites in human immunoglobulin heavy chain variable regions. Mol Immunol. 2000;37:107–13.

    Article  CAS  PubMed  Google Scholar 

  36. Anumula KR. Quantitative glycan profiling of normal human plasma derived immunoglobulin and its fragments Fab and Fc. J Immunol Methods. 2012;382:167–76.

    Article  CAS  PubMed  Google Scholar 

  37. Sabouri Z, Schofield P, Horikawa K, Spierings E, Kipling D, Randall KL, et al. Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity. Proc Natl Acad Sci USA. 2014;111:E2567–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhu D, McCarthy H, Ottensmeier CH, Johnson P, Hamblin TJ, Stevenson FK. Acquisition of potential N-glycosylation sites in the immunoglobulin variable region by somatic mutation is a distinctive feature of follicular lymphoma. Blood. 2002;99:2562–8.

    Article  CAS  PubMed  Google Scholar 

  39. Zhu D, Ottensmeier CH, Du MQ, McCarthy H, Stevenson FK. Incidence of potential glycosylation sites in immunoglobulin variable regions distinguishes between subsets of Burkitt’s lymphoma and mucosa-associated lymphoid tissue lymphoma. Br J Haematol. 2003;120:217–22.

    Article  CAS  PubMed  Google Scholar 

  40. Forconi F, Capello D, Berra E, Rossi D, Gloghini A, Cerri M, et al. Incidence of novel N-glycosylation sites in the B-cell receptor of lymphomas associated with immunodeficiency. Br J Haematol. 2004;124:604–9.

    Article  CAS  PubMed  Google Scholar 

  41. Zabalegui N, de Cerio AL, Inoges S, Rodriguez-Calvillo M, Perez-Calvo J, Hernandez M, et al. Acquired potential N-glycosylation sites within the tumor-specific immunoglobulin heavy chains of B-cell malignancies. Haematologica. 2004;89:541–6.

    CAS  PubMed  Google Scholar 

  42. Coelho V, Krysov S, Ghaemmaghami AM, Emara M, Potter KN, Johnson P, et al. Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins. Proc Natl Acad Sci USA. 2010;107:18587–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Linley A, Krysov S, Ponzoni M, Johnson PW, Packham G, Stevenson FK. Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells. Blood. 2015;126:1902–10.

    Article  CAS  PubMed  Google Scholar 

  44. Amin R, Mourcin F, Uhel F, Pangault C, Ruminy P, Dupre L, et al. DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma. Blood. 2015;126:1911–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bellotti V, Mangione P, Merlini G. Review: immunoglobulin light chain amyloidosis—the archetype of structural and pathogenic variability. J Struct Biol. 2000;130:280–9.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang C, Huang X, Li J. Light chain amyloidosis: Where are the light chains from and how they play their pathogenic role? Blood Rev. 2017;31:261–70.

    Article  CAS  PubMed  Google Scholar 

  47. Blancas-Mejia LM, Misra P, Dick CJ, Cooper SA, Redhage KR, Bergman MR, et al. Immunoglobulin light chain amyloid aggregation. Chem Commun. 2018;54:10664–74.

    Article  CAS  Google Scholar 

  48. Radamaker L, Karimi-Farsijani S, Andreotti G, Baur J, Neumann M, Schreiner S, et al. Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM. Nat Commun. 2021;12:6434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Murray DL, Puig N, Kristinsson S, Usmani SZ, Dispenzieri A, Bianchi G, et al. Mass spectrometry for the evaluation of monoclonal proteins in multiple myeloma and related disorders: an International Myeloma Working Group Mass Spectrometry Committee Report. Blood Cancer J. 2021;11:24.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Blancas-Mejia LM, Horn TJ, Marin-Argany M, Auton M, Tischer A, Ramirez-Alvarado M. Thermodynamic and fibril formation studies of full length immunoglobulin light chain AL-09 and its germline protein using scan rate dependent thermal unfolding. Biophys Chem. 2015;207:13–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Klimtchuk ES, Gursky O, Patel RS, Laporte KL, Connors LH, Skinner M, et al. The critical role of the constant region in thermal stability and aggregation of amyloidogenic immunoglobulin light chain. Biochemistry. 2010;49:9848–57.

    Article  CAS  PubMed  Google Scholar 

  52. Gonzalez-Andrade M, Becerril-Lujan B, Sanchez-Lopez R, Cecena-Alvarez H, Perez-Carreon JI, Ortiz E, et al. Mutational and genetic determinants of lambda6 light chain amyloidogenesis. FEBS J. 2013;280:6173–83.

    Article  CAS  PubMed  Google Scholar 

  53. Maritan M, Ambrosetti A, Oberti L, Barbiroli A, Diomede L, Romeo M, et al. Modulating the cardiotoxic behaviour of immunoglobulin light chain dimers through point mutations. Amyloid. 2019;26:105–6.

    Article  PubMed  Google Scholar 

  54. Rottenaicher GJ, Weber B, Ruhrnossl F, Kazman P, Absmeier RM, Hitzenberger M, et al. Molecular mechanism of amyloidogenic mutations in hypervariable regions of antibody light chains. J Biol Chem. 2021;296:100334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kazman P, Vielberg MT, Pulido Cendales MD, Hunziger L, Weber B, Hegenbart U, et al. Fatal amyloid formation in a patient’s antibody light chain is caused by a single point mutation. Elife. 2020;9:e52300.

  56. Weber B, Hora M, Kazman P, Gobl C, Camilloni C, Reif B, et al. The antibody light-chain linker regulates domain orientation and amyloidogenicity. J Mol Biol. 2018;430:4925–40.

    Article  CAS  PubMed  Google Scholar 

  57. Morgan GJ, Kelly JW. The kinetic stability of a full-length antibody light chain dimer determines whether endoproteolysis can release amyloidogenic variable domains. J Mol Biol. 2016;428:4280–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Morgan GJ, Usher GA, Kelly JW. Incomplete refolding of antibody light chains to non-native, protease-sensitive conformations leads to aggregation: a mechanism of amyloidogenesis in patients? Biochemistry. 2017;56:6597–614.

    Article  CAS  PubMed  Google Scholar 

  59. Rennella E, Morgan GJ, Kelly JW, Kay LE. Role of domain interactions in the aggregation of full-length immunoglobulin light chains. Proc Natl Acad Sci USA. 2019;116:854–63.

    Article  CAS  PubMed  Google Scholar 

  60. Moriconi C, Ordonez A, Lupo G, Gooptu B, Irving JA, Noto R, et al. Interactions between N-linked glycosylation and polymerisation of neuroserpin within the endoplasmic reticulum. FEBS J. 2015;282:4565–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Visentin C, Broggini L, Sala BM, Russo R, Barbiroli A, Santambrogio C, et al. Glycosylation tunes neuroserpin physiological and pathological properties. Int J Mol Sci. 2020;21:3235.

Download references

Acknowledgements

We thank Andrea Patrignani and staff of the Functional Genomic Center Zurich for PacBio library preparation and sequencing. This work was supported by grants from the Amyloidosis Foundation (MNu), the Italian Ministry of Health (Ricerca Finalizzata, grant #GR-2018-12368387) (MNu), the Italian Ministry of Research and Education (PRIN 20207XLJB2) (SR, GP), the CARIPLO Foundation (grant #2018-0257) (MNu), Fondazione ARISLA (project TDP-43-STRUCT) (SR), Cancer Research UK [C355/A26819], FC AECC and AIRC under the Accelerator Award Program (BP, GM, GP, MNu). We would like to acknowledge the use of the Boston University AL-Base, supported by HL68705, in this work.

Author information

Authors and Affiliations

  1. Department of Molecular Medicine, University of Pavia, Pavia, Italy

    Alice Nevone, Maria Girelli, Paolo Milani, Pasquale Cascino, Maggie Piscitelli, Marco Basset, Andrea Foli, Martina Nanci, Giulia Mazzini, Serena Caminito, Melania Antonietta Sesta, Simona Casarini, Paola Rognoni, Francesca Lavatelli, Luca Arcaini, Giampaolo Merlini, Giovanni Palladini & Mario Nuvolone

  2. Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Alice Nevone, Maria Girelli, Paolo Milani, Pasquale Cascino, Maggie Piscitelli, Pietro Benvenuti, Marco Basset, Andrea Foli, Martina Nanci, Giulia Mazzini, Serena Caminito, Melania Antonietta Sesta, Simona Casarini, Paola Rognoni, Francesca Lavatelli, Giampaolo Merlini, Giovanni Palladini & Mario Nuvolone

  3. Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Silvia Mangiacavalli, Claudio Salvatore Cartia, Pietro Benvenuti & Luca Arcaini

  4. Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CIBER-ONC number CB16/12/00369, Instituto de Investigacion Sanitaria de Navarra (IDISNA), Navarra, Spain

    Bruno Paiva & Ibai Goicoechea

  5. Dipartimento di Bioscienze, Università Degli Studi di Milano, Milan, Italy

    Valentina Speranzini & Stefano Ricagno

  6. Hematology, Department of Translational and Precision Medicine, Azienda Ospedaliera Policlinico Umberto I, Sapienza University of Rome, Rome, Italy

    Francesca Fazio & Maria Teresa Petrucci

  7. Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy

    Pier Paolo Olimpieri

  8. Institute of Molecular and Translational Cardiology, IRCCS Policlinico San Donato, Milan, Italy

    Stefano Ricagno

Authors
  1. Alice Nevone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Girelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Mangiacavalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bruno Paiva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paolo Milani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pasquale Cascino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maggie Piscitelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Valentina Speranzini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Claudio Salvatore Cartia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pietro Benvenuti
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ibai Goicoechea
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Francesca Fazio
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marco Basset
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Andrea Foli
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Martina Nanci
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Giulia Mazzini
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Serena Caminito
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Melania Antonietta Sesta
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Simona Casarini
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Paola Rognoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Francesca Lavatelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Maria Teresa Petrucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Pier Paolo Olimpieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Stefano Ricagno
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Luca Arcaini
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Giampaolo Merlini
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Giovanni Palladini
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Mario Nuvolone
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceived, designed, and supervised the project: MNu. Provided financial support to the project: SR, BP, GMe, GP, MNu. Performed clinical evaluations, provided patients’ samples and/or collected clinical data: SM, BP, PM, CCS, PB, IG, FF, MB, AF, MNa, MTP, LA, GMe, GP, MNu. Maintained biorepository: AN, MG, PC, SCam, MAS, SCas. Curated clinical database: AN, PB, FF, MNu. Retrieved published sequences and performed in silico analyses: AN, MG, PC, MP, PR, MNu. Processed bone-marrow samples, prepared sequencing libraries and analyzed LC sequences: AN, MG, PC, MP, MNu. Performed PNGase F digestion and Western blotting: MG, PC, MP. Performed mass spectrometry analyses: GMa, SCam, FL. Performed genomic analyses and Sanger sequencing: AN, MG, PC, MP, SCas. Performed molecular modeling and structural analyses: VS, SR. Performed statistical analyses: PPO. Prepared figures: AN, PC, MP, VS, SR, MNu. Wrote the paper: AN, MNu. Read, edited and approved the paper: All authors.

Corresponding authors

Correspondence to Giovanni Palladini or Mario Nuvolone.

Ethics declarations

Competing interests

PC, GP, and MNu are inventors on a patent application related to immunoglobulin sequencing.

Ethics approval and consent to participate

Clinical records and biological samples were from subjects referred to the Italian Amyloid Center or to the Department of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy and to the University Hospital of Navarra, Pamplona, Spain for a diagnostic workout in the suspicion of systemic AL amyloidosis or MM. Per the Declaration of Helsinki, all patients gave their written informed consent for the use of their clinical data and biological samples for research purposes, and this study was approved by the local Institutional Review Board.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nevone, A., Girelli, M., Mangiacavalli, S. et al. An N-glycosylation hotspot in immunoglobulin κ light chains is associated with AL amyloidosis. Leukemia 36, 2076–2085 (2022). https://doi.org/10.1038/s41375-022-01599-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-022-01599-w

Search

Advanced search

Quick links