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<p>Monoclonal free light chains drive diverse renal pathologies in plasma cell dyscrasias. However, the mechanism of light chain proximal tubulopathy remains poorly understood because sequence data are scarce. Here we characterize full-length kappa free light chains from five patients with light chain proximal tubulopathy, four of whom had intracellular crystals. All showed the highest homology to the IGKV1-33 germline, while crystal-forming light chains contained distinct single-residue substitutions. These light chains generated a stable ~12-kDa fragment resistant to digestion by cathepsin B and D, a pattern not observed in non-crystal-forming light chains. Mechanistically, a single-residue substitution contributed substantially to cathepsin D resistance and stable fragment formation. In vivo comparison of recombinant κWJJ and its single-amino acid mutant further supported an important role for this substitution in intracellular crystal formation. These findings establish a sequence-based link between impaired lysosomal processing and crystal accumulation in light chain proximal tubulopathy.</p>

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Cathepsin resistance mediated by key amino acid substitutions drives intracellular crystallization in light chain proximal tubulopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Xin Wang,
  • Shuang Wang,
  • Chu-qiao Wang,
  • Yue-yue Zhu,
  • Xin Zhang,
  • Jin Xu,
  • Yi Liu,
  • Xiao-juan Yu,
  • Su-xia Wang,
  • Li Yang,
  • Fu-de Zhou,
  • Ming-hui Zhao

摘要

Monoclonal free light chains drive diverse renal pathologies in plasma cell dyscrasias. However, the mechanism of light chain proximal tubulopathy remains poorly understood because sequence data are scarce. Here we characterize full-length kappa free light chains from five patients with light chain proximal tubulopathy, four of whom had intracellular crystals. All showed the highest homology to the IGKV1-33 germline, while crystal-forming light chains contained distinct single-residue substitutions. These light chains generated a stable ~12-kDa fragment resistant to digestion by cathepsin B and D, a pattern not observed in non-crystal-forming light chains. Mechanistically, a single-residue substitution contributed substantially to cathepsin D resistance and stable fragment formation. In vivo comparison of recombinant κWJJ and its single-amino acid mutant further supported an important role for this substitution in intracellular crystal formation. These findings establish a sequence-based link between impaired lysosomal processing and crystal accumulation in light chain proximal tubulopathy.