Modulating the cardiotoxic behaviour of immunoglobulin light chain dimers through point mutations

Maritan, Martina; Ambrosetti, Arianna; Oberti, Luca; Barbiroli, Alberto; Diomede, Luisa; Romeo, Margherita; Lavatelli, Francesca; Sormanni, Pietro; Palladini, Giovanni; Bolognesi, M.; Merlini, Giampaolo; Ricagno, Stéfano

doi:10.1080/13506129.2019.1583185

Cited by 5 publications

(4 citation statements)

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“…From a biochemical and biophysical point of view, a growing body of evidence indicates that LC amyloidogenicity correlates with several biophysical properties, including reduced thermodynamic/kinetic stability and protein dynamics. Moreover, beta strands D and E are one hotspot for those mutations and modifications that contribute to altered protein stability and subsequent variation of aggregation propensity [51][52][53][54][55][56][57][58][59][60] .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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 Nglycosylation 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…The intrinsic propensity of a monoclonal LC for pathological aggregation is determined by both the encoding V L gene segment ( 167 – 171 ), and the somatic mutations ( 54 , 152 , 164 , 172 – 176 ). The encoding IGV L gene segment may confer to the LC the propensity to aggregate in a specific form, as well as in a specific organ or tissue (organ tropism).…”

Section: Diseases Caused By Immunoglobulin Light Chains Misfolding An...mentioning

confidence: 99%

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe

et al. 2023

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The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protective mechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (VL) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces.

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“…A model from a recent study based on somatic mutations in IgL displays high sensitivity and specificity to predict the free light chain toxicity [ 96 ]. Moreover, the introduction of specific point mutations in the IgL locus could attenuate the free light chain toxicity [ 96 – 98 ], which underlines the possibility of gene therapy in AL.…”

Section: Genomic Alterations Related To Amyloid Formationmentioning

confidence: 99%

Genetic pathogenesis of immunoglobulin light chain amyloidosis: basic characteristics and clinical applications

2021

Exp Hematol Oncol

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Immunoglobulin light chain amyloidosis (AL) is an indolent plasma cell disorder characterized by free immunoglobulin light chain (FLC) misfolding and amyloid fibril deposition. The cytogenetic pattern of AL shows profound similarity with that of other plasma cell disorders but harbors distinct features. AL can be classified into two primary subtypes: non-hyperdiploidy and hyperdiploidy. Non-hyperdiploidy usually involves immunoglobulin heavy chain translocations, and t(11;14) is the hallmark of this disease. T(11;14) is associated with low plasma cell count but high FLC level and displays distinct response outcomes to different treatment modalities. Hyperdiploidy is associated with plasmacytosis and subclone formation, and it generally confers a neutral or inferior prognostic outcome. Other chromosome abnormalities and driver gene mutations are considered as secondary cytogenetic aberrations that occur during disease evolution. These genetic aberrations contribute to the proliferation of plasma cells, which secrete excess FLC for amyloid deposition. Other genetic factors, such as specific usage of immunoglobulin light chain germline genes and light chain somatic mutations, also play an essential role in amyloid fibril deposition in AL. This paper will propose a framework of AL classification based on genetic aberrations and discuss the amyloid formation of AL from a genetic aspect.

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Modulating the cardiotoxic behaviour of immunoglobulin light chain dimers through point mutations

Cited by 5 publications

References 4 publications

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

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

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe

Genetic pathogenesis of immunoglobulin light chain amyloidosis: basic characteristics and clinical applications

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