Immunoglobulin Light Chain Gene Constant Region Is An Invariable Part of Amyloid Deposits in AL Amyloidosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3128-3128
Author(s):  
Jason D. Theis ◽  
Julie A. Vrana ◽  
Jeffrey D. Gamez ◽  
Angela Dispenzieri ◽  
Stephen R. Zeldenrust ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Light Chain ◽  
Proteomic Analysis ◽  
Laser Microdissection ◽  
Variable Region ◽  
Al Amyloidosis ◽  
Constant Region ◽  
Immunoglobulin Light Chain ◽  
Amyloid Deposits ◽  
Region I

Abstract Background: Amyloidosis caused by immunoglobulin light chain (IGLC) deposition, so-called AL-type or primary amyloidosis, is the most common type of amyloidosis. It has been long believed that IGLC variable regions form the core of the AL-type amyloid deposits and peptides derived from IGLC constant region peptides are only occasionally integrated into this core. For this reason, the scientific effort to identify thge risk factors for development of AL amyloidosis and the biochemical characteristics amyloid deposits has focused on IGLC variable region derived proteins. To understand the peptide constituents of AL amyloidosis better, we undertook a comprehensive study of AL amyloidosis using a novel mass spectrometry based proteomic analysis approach. Methods: Paraffin embedded tissue from 100 cases of AL amyloidosis was studied. In each case amyloid type was previously established by clinical and pathological examination. Congo red stained paraffin sections were prepared and amyloid deposits were microdissected by laser microdissection microscopy. The microdissected tissue fragments were processed and trypsin digested into peptides. The peptides were analyzed by nano-flow liquid chromatography electrospray tandem mass spectrometry (LC-MS/MS). The resulting LC-MS/MS data were correlated to theoretical fragmentation patterns of tryptic peptide sequences from the Swissprot database using Scaffold (Mascot, Sequest, and X!Tandem search algorithms). Peptide identifications were accepted if they could be established at greater than 90.0% probability and protein identifications were accepted if they could be established at greater than 90.0% probability and contain at least 2 identified spectra. The identified proteins were subsequently examined for the presence or absence of amyloid related peptides. Results and Discussion: LC-MS/MS gave peptide profiles consistent with AL amyloidosis in each case. The analysis showed IGLC-lambda deposition in 66 cases and IGLC-kappa deposition in 34 of cases. In each case, LC MS/MS confirmed the previous clinicopathological diagnosis. Interestingly peptides representing IGLC constant region were present in each case. Using this LC-MS/MS methodology, theoretically it is possible to cover 78% of the IGLC-lambda and 87% IGLC-kappa constant regions. In our samples, the average coverage of the IGLC-lambda and IGLC-kappa constant regions were 40% (range 14–78%)and 55% (range 16–87%) respectively. Additionally, the distribution of the peptides suggested that in the majority of the cases whole of the IGLC constant region was deposited. LC MS/MS also identified IGLC-lambda variable region peptides in 37 of 66 cases and IGLC-kappa variable region peptides in 29 of 34 cases studied. The variable region coverage was more restricted and the peptides identified were frequently within the framework segments. It is likely that the peptides derived from CDR segments were present but not detected by the methodology as somatic hypermutation randomly alters the amino acid sequence in the CDR segments and such new sequences are not available in public databases used by algorithms for peptide identification. In the cases with the IGLC variable region hits, it was also possible to assign variable region family usage. IGLC-lambda cases frequently used IGLC-lambda variable region I, II and III families whereas, in IGLC-kappa cases, IGLC-kappa variable region I and III families dominated. Conclusions: AL amyloidosis can be accurately diagnosed using laser microdissection and LC-MS/MS based proteomic analysis in routine clinical specimens. AL amyloidosis invariably contains IGLC constant region peptides and, frequently, the whole of the constant region is deposited. This finding suggests that studies on molecular pathogenesis of amyloidosis should not only consider the IGLC-variable region but also the constant region. It is possible to identify IGLC variable region family usage in AL amyloidosis using LC MS/MS based proteomic analysis. In the clinical setting, this information may be helpful in predicting organ distribution and clinical outcome.

Deposition of Lambda Chain Constant Region within AL-Amyloid Lesion

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3348-3348
Author(s):  
Hiroyuki Hata ◽  
Masayoshi Tasaki ◽  
Konen Obayashi ◽  
Taro Yamashita ◽  
Yukio Ando ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Light Chain ◽  
Mass Spectrometry Analysis ◽  
Light Chains ◽  
High Dose ◽  
Al Amyloidosis ◽  
Constant Region ◽  
Rt Pcr ◽  
Immunoglobulin Light Chain ◽  
Lambda Light Chain

Abstract [Introduction] Diagnosis of AL amyloidosis is dependent on the proof of light chains in amyloid lesions. However, immunostaining does not always successfully prove the presence of light chains in lesions in AL amylidosis patients. Here we report that the constant region of immunoglobulin lambda light chain (IGLC2) is seen in amyloid lesions where no positive signals are found with regular immunostaining. [Materials and Methods] Amyloid samples were stained with anti-human lambda light chain antibody (DAKO PO-0130) and analyzed with mass-spectrometry combining laser micro-dissection. Bone marrow samples were obtained from patients with amyloidosis, who gave written informed consent, and were subjected to plasma cell purification using CD138-immunomagnetic beads. Expression of immunoglobulin light chain mRNA was examined with RT-PCR. Anti-human IGLL5 antibody, capable of detecting immunoglobulin light chain constant region 2 (IGLC2) in paraffin embedded samples, was utilized. [Results and Discussion] We performed immunostaining for immunoglobulin light chains with 18 samples and found that six and eight cases were positive for kappa and lambda light chains, respectively, whereas light chains were not detected in remaining four cases (immunostaining-negative amyloidosis; INA). However, interestingly, mass spectrometry analysis revealed the presence of IGLC2 in all of the INA cases. RT-PCR analysis revealed the presence of IGLC2 mRNA in plasma cells from such INA cases. Surprisingly, amyloid lesions in all of the INA cases were positively stained with anti-IGLL5 antibody, whereas no staining was found in other samples positively stained with DAKO PO-0130. These observations suggest that the deposition of IGLC2 may cause AL amyloidosis, which otherwise could not be diagnosed with regular immunostaining. Although high dose chemotherapy produced hematological remission, half of such cases died within one year, suggesting irreversible and life-threatening amyloid fibril depositions in critical organs in IGLC2-related cases. We further examined additional twelve cases with AL amyloidosis to determine the incidence of IGLC2-related amyloidosis by immunostaining. With regular immunostaining, kappa and lambda chain were found in three and five cases, respectively. Interestingly, the remaining four cases were negative with regular immunostaining but positive with anti-IGLL5 antibody. Taken these observations together, eight IGLC2-related amyloidosis cases and thirteen lambda type amyloidosis were identified. Thus, the incidence of IGLC2-related amyloidosis should be approximately 38% (8/21) among lambda type AL amyloidosis. We conclude that diagnosis of IGLC2-related AL amyloidosis was possible only with the use of anti-IGLL5 antibody, but not with regular immunostaining. Given the relatively high incidence and often poor prognosis of IGLC2-related amyloidosis, it is important that this clinical entity is recognized to potentially improve outcomes of treatments. Analysis of mechanisms regulating amyloid formation with IGLC2 peptides is currently underway. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hereditary systemic immunoglobulin light-chain amyloidosis

Blood ◽  
2015 ◽  
Vol 125 (21) ◽  
pp. 3281-3286 ◽  
Author(s):  
Merrill D. Benson ◽  
Juris J. Liepnieks ◽  
Barbara Kluve-Beckerman
Keyword(s):  
Light Chain ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Constant Region ◽  
Immunoglobulin Light Chain ◽  
Region Gene ◽  
Dna Analyses ◽  
Key Points ◽  
Constant Region Gene ◽  
Immunoglobulin Light Chain Amyloidosis

Key Points Protein and DNA analyses reveal that mutation in the immunoglobulin κ light-chain constant region gene may cause hereditary amyloidosis. Sequencing of immunoglobulin light-chain constant region genes is indicated for patients with AL amyloidosis and no evidence of a plasma cell dyscrasia.

Frequency of Amyloid Subtyping Among Patients with Immunoglobulin Light-Chain Amyloidosis Referred for High-Dose Chemotherapy and Autologous Stem Cell Transplant

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5601-5601
Author(s):  
Andrew J. Cowan ◽  
David G. Coffey ◽  
Teresa S. Hyun ◽  
Pamela S. Becker ◽  
Damian J. Green ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Plasma Cell ◽  
Light Chain ◽  
Congo Red ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Immunoglobulin Light Chain ◽  
Organ Systems

Abstract Background: The amyloidoses comprise a heterogeneous group of diseases characterized by misfolding of amyloidogenic proteins and subsequent deposition as amyloid fibrils. To date, over 30 proteins are known to be amyloidogenic (Sipe Amyloid 2014). Immunoglobulin light chain (AL) amyloidosis, a plasma cell dyscrasia, is the most common subtype. The standard diagnostic algorithm in AL amyloidosis is to obtain a biopsy of a clinically involve organ, and once Congo red positivity is confirmed, perform subtyping analyses with immunohistochemistry or mass spectrometry. Accurate subtyping of amyloidosis is essential to appropriate treatment, as misdiagnosis occurs in up to 10% of patients and may lead to inappropriate administration of chemotherapy (Comenzo Blood 2006; Lachmann NEJM 2002). We sought to determine the patterns of amyloid subtyping among patients with a diagnosis of AL amyloidosis referred to a tertiary referral center for HDM/SCT. Methods: Sequential patients with confirmed amyloidosis, age ≥ 18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were eligible. Presence of a Congo red-positive biopsy for each patient referred for transplant was confirmed and the pathology reports and medical records were reviewed to determine if subtyping was performed, and which modality was used. Results: Fifty-one patients with AL amyloidosis were referred for transplant; of these, 45 proceeded with HDM/SCT. The organ systems most commonly involved were renal in 34/51, and gastrointestinal in 5/51. Of the biopsies, subtyping was performed in 35 (68.6%), and no subtyping was performed in 16 patients (31.3%). Immunofluorescence was the most common modality used for subtyping in 33 biopsies (94.2%) and laser capture/mass spectrometry (LC/MS) was used in 2 patients (5.7%). All patients had evidence of a clonal plasma cell dyscrasia by bone marrow biopsy and peripheral blood testing. Of the patients without subtyping, 8 (50%) were diagnosed before 2008. Discussion: Misdiagnosis of amyloidosis due to a lack of appropriate subtyping is a well-described and ongoing problem for patients with amyloidosis. These data suggest that definitive subtyping is still not routinely performed in the evaluation of amyloidosis. At our center, efforts to standardize the evaluation of Congo-red positive biopsies using definitive typing are underway. Disclosures Gopal: Seattle Genetics: Research Funding.

A Clinical Test for the Identification of Amyloid Proteins in Biopsy Specimens by a Novel Method Based on Laser Microdissection and Mass Spectrometry.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1480-1480 ◽  
Author(s):  
Julie A. Vrana ◽  
Jeffrey D. Gamez ◽  
Jason D. Theis ◽  
Timothy B. Plummer ◽  
Robert H. Bergen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Bone Marrow ◽  
Light Chain ◽  
Laser Microdissection ◽  
Clinical Test ◽  
Immunoglobulin Light Chain ◽  
Accurate Identification ◽  
Biopsy Specimens ◽  
Specificity And Sensitivity ◽  
Novel Method

Abstract The management of systemic amyloidosis relies on the treatment of the underlying etiology and differs radically for different amyloid types. Therefore, given that at least 25 different proteins have been associated with amyloidosis, accurate identification of proteins deposited as amyloid fibrils is an important clinical problem. In this study, we describe a novel method that can characterize amyloid subtypes using laser microdissection (LMD) and mass spectrometry (MS) on routinely processed paraffin-embedded tissues. The study used 60 cases consisting of 16 transthyretin, 9 serum amyloid-associated protein, 20 immunoglobulin light chain lambda, 5 immunoglobulin light chain kappa, and 10 amyloid negative control samples. The biopsy specimens studied included heart, kidney, gastrointestinal tract, lung and decalcified bone marrow specimens. The amyloid type in all cases was previously characterized based on clinical findings, immunohistochemistry and, where indicated, by molecular testing for transthyretin mutations. Amyloid plaques were captured from an 10 micron paraffin section exhibiting positive Congo Red staining using LMD. Proteins were extracted, digested with trypsin and identified following MS/MS using the Mascot search algorithm analysis. MS correctly identified each of the 4 types of amyloidosis analyzed. Serum Amyloid P component and Apolipoprotein E were also identified as constituents of the amyloid deposition. The analysis was successful on all tissue types including decalcified bone marrow specimens and small biopsy specimens such as endomycardial biopsies and renal biopsies. The use of LMD from paraffin embedded biopsies and subsequent analysis by MS allows identification of the type of amyloid protein deposited with high specificity and sensitivity. This method promises to be a clinical test for accurate identification of amyloid proteins in routinely processed biopsy specimens and overcomes many of the specificity and sensitivity issues associated with current methods such as immunohistochemistry.

Mass Spectrometry-Based Proteomics Reveals Distinct Immunoglobulin Light Chain Variable Region Usage In Systemic Versus Localized AL Amyloidosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3142-3142
Author(s):  
Oana M Mereuta ◽  
Surendra Dasari ◽  
Jason D Theis ◽  
Julie A Vrana ◽  
Karen L Grogg ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Gene Family ◽  
Light Chain ◽  
Gene Families ◽  
Al Amyloidosis ◽  
Gi Tract ◽  
Immunoglobulin Light Chain ◽  
Protein Mass ◽  
V Region ◽  
Region Usage

Abstract Background Immunoglobulin light chain-associated amyloidosis (AL) is caused by deposition of immunoglobulin light chain molecules with unique, clonotypic variable (V) regions. Detection and identification of the V region, however, has been challenging due heterogeneity inherent in V regions. We developed a new method for detecting IGKV and IGLV region fragments in AL deposits using protein mass spectrometry and novel bioinformatics approach. We report distinct IGKV and IGLV usage in localized versus systemic AL. Methods Shotgun protein mass spectrometry on amyloid plaques was performed as previously described (Blood. 2009; 114: 4957-9). Peptide tandem mass spectra (MS/MS) were searched against a composite sequence database containing SwissProt's human complete proteome augmented with 1764 IG V region sequences obtained from ImMunoGeneTics database and a Mayo Clinic internal database. Reversed sequences were appended to the database for estimating identification false discovery rates (FDRs). Peptide identifications were processed with Scaffold software. Confident protein identifications (probability > 0.9) with at least one unique peptide identifications and five MS/MS matches were considered. Detected variable gene family (if any) with most number of peptide and spectral matches is considered to be present in the deposit. The method was first validated in 8 cases of AL amyloidosis with known IGKV and IGLV region sequences and then applied on 1238 systemic and 393 localized AL cases. Differences between groups were measured by generating hypergeometric p-values. Results In all 8 AL cases with known IGKV and IGLV region usage, gene family identified in the AL deposit via proteomics matched the gene family inferred from bone marrow plasma cells by Sanger sequencing of IGLC genes. Armed with this method, we analyzed the amyloid proteomics data from 1238 patients with systemic AL amyloidosis and 393 patients with localized AL amyloidosis. The anatomical site distribution in systemic cohort was 296 GI tract, 364 heart, 225 kidney, 81 liver and 272 fat aspirate; Localized cohort has 78 bladder, 158 lung and 157 skin cases. Figure 1 shows the normalized frequency of the variable gene families detected between the systemic and localized AL amyloidosis. For AL-kappa, KV1 was more prevalent in systemic cases when compared to localized cases (p=7.2E-12) suggesting KV1 clones as a hallmark for systemic AL-kappa amyloidosis. KV3 was more frequently seen in localized AL-kappa cases when compared to systemic AL-kappa cases (p =2.8E-11). For AL-lambda, LV1 and LV2 gene families were more prevalent in localized cases when compared to systemic cases (p= 0.039 and 2.7E-05). LV6 was more prevalent in systemic AL-lambda cases (p=1.4E-07). We also detected a higher incidence of mixed AL/AH type in localized AL (18%) when compared to systemic AL (5%; Odds Ratio=4.2673, p<0.0001). We next turned to the organ specific IGKV and IGLV gene family usage patterns in patients with localized amyloidosis. For 147 localized AL-kappa cases, KV3 was most dominant in lung (64%) and KV1 was dominant in skin (38%). For 246 localized AL-lambda cases, LV2 was most prevalent in lung (34%) and LV3 was most prevalent in skin (36%). For bladder, both LV1 and LV2 had comparable prevalence (42% and 32%). For 361 systemic AL-kappa cases, KV1 consistently ranked at the top of gene families used in GI tract (55%), heart (71%), kidney (59%), liver (75%) and fat aspirate (50%). For 877 systemic AL-lambda cases, LV2 was predominant in GI tract (30%), LV3 in heart (35%) and LV6 in kidney (33%). The prevalence of LV1, LV2 and LV3 in liver is comparable (36%, 22% and 31%). LV6 and LV3 had comparable prevalence (22% and 24%) in AL-lambda fat aspirates. Conclusion The novel proteomics method detects IGLC V family usage in large cohorts of AL patients. It identifies unique profiles in systemic and localized cases, and in different organ sites. This information will be helpful in determining systemic versus localized nature of AL amyloidosis at diagnosis and to assess risk of specific end organ involvement. We found also a strong association between IGKV and IGLV gene usage and organ involvement. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Solid state NMR assignments of a human λ-III immunoglobulin light chain amyloid fibril

2020 ◽  
Author(s):  
Tejaswini Pradhan ◽  
Karthikeyan Annamalai ◽  
Riddhiman Sarkar ◽  
Ute Hegenbart ◽  
Stefan Schönland ◽  
...  
Keyword(s):  
Solid State ◽  
Light Chain ◽  
Solid State Nmr ◽  
Cardiac Involvement ◽  
Gene Segment ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Fibril Structure ◽  
Amyloid Deposits ◽  
Complementarity Determining Regions

Abstract The aggregation of antibody light chains is linked to systemic light chain (AL) amyloidosis, a disease where amyloid deposits frequently affect the heart and the kidney. We here investigate fibrils from the λ-III FOR005 light chain (LC), which is derived from an AL-patient with severe cardiac involvement. In FOR005, five residues are mutated with respect to its closest germline gene segment IGLV3-19 and IGLJ3. All mutations are located close to the complementarity determining regions (CDRs). The sequence segments responsible for the fibril formation are not yet known. We use fibrils extracted from the heart of this particular amyloidosis patient as seeds to prepare fibrils for solid-state NMR. We show that the seeds induce the formation of a specific fibril structure from the biochemically produced protein. We have assigned the fibril core region of the FOR005-derived fibrils and characterized the secondary structure propensity of the observed amino acids. As the primary structure of the aggregated patient protein is different for every AL patient, it is important to study, analyze and report a greater number of light chain sequences associated with AL amyloidosis.

Diagnosis Of Amyloidosis Subtype By Laser-Capture Microdissection (LCM) and Tandem Mass Spectrometry (MS) Proteomic Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5295-5295
Author(s):  
Peter Mollee ◽  
Patricia Renaut ◽  
Samuel Boros ◽  
Dorothy Loo ◽  
Michelle Hill
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Light Chain ◽  
Proteomic Analysis ◽  
Diagnostic Methods ◽  
Serum Amyloid ◽  
Tandem Ms ◽  
Tandem Mass ◽  
Genetic Studies ◽  
Amyloid Deposits

Abstract Aim Correct identification of the protein that is causing amyloidosis is crucial for clinical management. Current standard diagnostic methods have limited ability to detect the full range of amyloid forming proteins. We assessed combining specific sampling of amyloid deposits by LCM and analysis of tryptic digests by tandem MS proteomic analysis to determine whether the majority of amyloidosis clinical samples can be correctly classified as reported by the Mayo Clinic pathology department. Methods We studied 58 cases of well characterised amyloid deposition and 10 cases in which the amyloid subtype was unable to be diagnosed with confidence. For all specimens, 10µm sections of formalin-fixed paraffin embedded tissue were stained with Congo Red using a standard technique. LCM was performed using an Arcturus XT instrument with an infrared capture laser. Proteins were digested with trypsin and peptides were analysed by nano-liquid chromatography-coupled tandem mass spectrometry using a Chip CUBE-QTOF. Database searching was performed using Spectrum Mill (Agilent) with the NCBInr human protein database. Protein identification cut-offs were protein score > 11, peptide score > 10 and % scored peak intensity >60. Results Biopsy sites included: GIT (n=16), cardiac (n=12), soft tissue (n=8), renal (n=9), liver (n=3) and other (n=20). The amyloid subtype was able to be determined in 64 cases analysed. In 7 of these cases a second sample or second LCM was required as the first analysis was non-diagnostic. In 4 cases the amyloidogenic protein was not identified mostly due to the amyloid deposits being very small. Proteins identified included immunoglobulin light chain (localised amyloid n=6, systemic AL n=32), transthyretin (senile amyloid n=17, hereditary ATTR n=2), serum amyloid A (AA n=4), fibrinogen (AFib n=1), TGFb (corneal lattice amyloid n=1) and semenogelin (seminal vesicle amyloid n=1). Three diagnostically challenging cases are detailed as examples of the utility of LCM and tandem MS. The first case had extensive gastrointestinal amyloidosis and no evidence of clonal light chain disease; negative kappa, lambda, SAA and transthyretin immunohistochemistry; and negative genetic studies. Tandem MS revealed immunoglobulin lambda light chain type. The second diagnostically challenging case had: isolated renal amyloidosis with a positive AA stain and kappa restricted serum free light chains. Tandem MS revealed serum amyloid A2 protein. The third case had: cardiac, neurological and gastrointestinal involvement; and equivocal immunohistochemistry. Tandem MS demonstrated transthyretin and genetic studies showed a A97S ATTR mutation. Various other proteins were identified by tandem MS in amyloid extracts. Of particular interest is the presence of proteins typically known to be co-located in amyloid deposits which helps confirm that the microdissected tissue is amyloid. Typical amyloid-associated proteins were identified in the following number of cases: SAP (n=36), apolipoprotein A4 (n=42), vitronectin (n=44), apolipoprotein E (n=40) and clusterin (n=21). Various types of collagen were frequently present (n=29) and various, presumably contaminating, keratins were identified (n=24). Conclusion LCM and tandem MS allows correct typing of amyloid deposits in the majority of clinical biopsy samples. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IGVL gene region usage correlates with distinct clinical presentation in IgM vs non-IgM light chain amyloidosis

2021 ◽  
Vol 5 (8) ◽  
pp. 2101-2105
Author(s):  
Surbhi Sidana ◽  
Surendra Dasari ◽  
Taxiarchis V. Kourelis ◽  
Angela Dispenzieri ◽  
David L. Murray ◽  
...  
Keyword(s):  
Light Chain ◽  
Clinical Presentation ◽  
Variable Region ◽  
Immunoglobulin M ◽  
Al Amyloidosis ◽  
Amyloid Deposits ◽  
Peripheral Nerve Involvement ◽  
Gene Usage ◽  
Region Usage ◽  
Organ Tropism

Abstract Patients with immunoglobulin M (IgM) light chain (AL) amyloidosis have a distinct clinical presentation compared with those with non-IgM amyloidosis. We hypothesized that differential immunoglobulin light-chain variable region (IGVL) gene usage may explain the differences in organ involvement, because IGVL usage correlates with organ tropism. IGVL usage was evaluated by mass spectrometry of amyloid deposits (IgM, n = 45; non-IgM, n = 391) and differed across the 2 groups. In the λ family, LV2-08 (13% vs 2%; P &lt; .001) and LV2-14 (36% vs 10%; P &lt; .001) usage was more common in IgM vs non-IgM amyloidosis, whereas LV1-44 (0% vs 10%; P = .02) and LV6-57 (2% vs 18%; P = .004) usage was less common. In the κ family, there was a trend toward higher KV4-01 (11% vs 4%; P = .06) usage in IgM amyloidosis. IGVL usage correlated with disease characteristics/organ tropism. LV2-14 (more common in IgM amyloidosis) has historically been associated with peripheral nerve involvement and lower light chain burden, which were more frequent in IgM amyloidosis. LV1-44 (less common in IgM), associated with cardiac involvement, was less frequent in IgM patients. LV6-57 (less common in IgM) is associated with t(11;14), which was less frequent in IgM patients. In conclusion, IGVL gene usage differs in patients with IgM vs non-IgM amyloidosis and may explain the distinct clinical presentation.

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