Sequence diversity of kappa light chains from patients with AL amyloidosis and multiple myeloma.

IF 5.2 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Amyloid-Journal of Protein Folding Disorders Pub Date : 2024-06-01 Epub Date: 2024-01-11 DOI:10.1080/13506129.2023.2295221

Sarah Schreiner, Natalie Berghaus, Alexandra M Poos, Marc S Raab, Britta Besemer, Roland Fenk, Hartmut Goldschmidt, Elias K Mai, Carsten Müller-Tidow, Niels Weinhold, Ute Hegenbart, Stefanie Huhn, Stefan O Schönland

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Abstract

Background: AL amyloidosis (AL) results from the misfolding of immunoglobulin light chains (IG LCs). Aim of this study was to comprehensively analyse kappa LC sequences from AL patients in comparison with multiple myeloma (MM).

Objective: We analysed IGKV/IGKJ usage and associated organ tropism and IGKV1/D-33 in terms of mutational analysis and theoretical biochemical properties.

Material and methods: cDNA and bulk RNA sequencing of the LCs of AL and MM patients.

Results: We studied 41 AL and 83 MM patients showing that IGKV1 was most expressed among kappa AL and MM, with higher frequency in AL (80% vs. 53%, p = .002). IGKV3 was underrepresented in AL (10% vs. 30%, p = .014). IGKJ2 was more commonly used in AL than in MM (39% vs. 29%). Patients with IGKV1/D-33 were associated with heart involvement (75%, p = .024). IGKV1/D-33-segments of AL had a higher mutation count (AL = 12.0 vs. MM = 10.0). FR3 and CDR3 were most frequently mutated in both, with a median mutation count in FR3 being the highest (AL = 4.0; MM = 3.5) and one mutation hotspot (FR3 (83I)) for IGKV1/D-33/IGKJ2 was associated with cardiac involvement.

Conclusion: This study confirmed that germline usage has an influence on AL amyloidosis risk and organ involvement.

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AL 淀粉样变性和多发性骨髓瘤患者卡帕轻链的序列多样性。

背景：肌钙蛋白淀粉样变性（AL）是免疫球蛋白轻链（IG LCs）错误折叠的结果。本研究旨在全面分析 AL 患者与多发性骨髓瘤（MM）患者的卡帕 LC 序列：材料与方法：对 AL 和 MM 患者的 LC 进行 cDNA 和大量 RNA 测序：我们对41例AL和83例MM患者进行了研究，结果显示，IGKV1在kappa AL和MM中表达最多，在AL中的频率更高（80%对53%，p = .002）。IGKV3在AL中的比例较低（10%对30%，P = .014）。IGKJ2在AL中的使用率高于MM（39% vs. 29%）。IGKV1/D-33患者与心脏受累有关（75%，p = .024）。IGKV1/D-33-段的AL患者的突变数量更高（AL = 12.0 vs. MM = 10.0）。两者中FR3和CDR3的突变频率最高，其中FR3的中位突变数最高（AL = 4.0; MM = 3.5），IGKV1/D-33/IGKJ2的一个突变热点（FR3 (83I)）与心脏受累有关：本研究证实，种系遗传对AL淀粉样变性风险和器官受累有影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Amyloid-Journal of Protein Folding Disorders 生物-生化与分子生物学

CiteScore

10.60

自引率

10.90%

发文量

审稿时长

6-12 weeks

期刊介绍： Amyloid: the Journal of Protein Folding Disorders is dedicated to the study of all aspects of the protein groups and associated disorders that are classified as the amyloidoses as well as other disorders associated with abnormal protein folding. The journals major focus points are: etiology, pathogenesis, histopathology, chemical structure, nature of fibrillogenesis; whilst also publishing papers on the basic and chemical genetic aspects of many of these disorders. Amyloid is recognised as one of the leading publications on amyloid protein classifications and the associated disorders, as well as clinical studies on all aspects of amyloid related neurodegenerative diseases and major clinical studies on inherited amyloidosis, especially those related to transthyretin. The Journal also publishes book reviews, meeting reports, editorials, thesis abstracts, review articles and symposia in the various areas listed above.