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<p>Achalasia is a rare esophageal motility disorder of poorly understood etiology. Here, we perform a large trio-based whole-genome sequencing study of achalasia and identify a recessively inherited frameshift variant in <i>FAM129C</i> (p.Ala454fs). A CRISPR/Cas9-engineered <i>Fam129c</i>-mutant mouse model recapitulating key features of achalasia was established, including growth retardation, elevated lower esophageal sphincter (LES) pressure, and selective loss of inhibitory neurons. Multi-omic analyses revealed substantial B cell expansion and activation within the LES, accompanied by enhanced humoral immune responses. Time-course experiments demonstrated that B cell accumulation preceded overt neuronal loss, while B cell depletion via anti-CD20 antibodies or intravenous immunoglobulin treatment partially rescued the phenotypes. Further protein profiling and cell-based assays suggested that the GABA<sub>A</sub> receptor may represent one potential neuronal antigen targeted by circulating autoantibodies. Together, these findings identify FAM129C as a genetic contributor to achalasia and support a neuroimmune mechanism in which B cell activation and autoantibody-mediated responses contribute to inhibitory neuronal injury. These results provide important insights into achalasia pathogenesis and highlight the potential of immunomodulatory strategies for disease intervention in the early stage.</p>

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A frameshift variant in FAM129C contributes to achalasia through B cell responses against the GABAA receptor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月25日

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  • Xiao-Qing Li,
  • Xin-Yue Li,
  • Wei-Feng Chen,
  • Zi-Ye Xu,
  • Zu-Qiang Liu,
  • Yun Wang,
  • Ji-Yuan Zhang,
  • Ya-Yun Gu,
  • Lu Yao,
  • Yan-Fang Tan,
  • Xiang-Jun Chen,
  • Bo Deng,
  • Ke-Hao Wang,
  • Jia-Qi Xu,
  • Meng-Jiang He,
  • Zi-Han Geng,
  • Ke-Yang Fan,
  • Zhao-Chao Zhang,
  • Li Wang,
  • An-Yi Xiang,
  • Hai-Ting Pan,
  • Zhi-Bin Hu,
  • Yun-Li Xie,
  • Cheng Wang,
  • Ping-Hong Zhou,
  • Quan-Lin Li

摘要

Achalasia is a rare esophageal motility disorder of poorly understood etiology. Here, we perform a large trio-based whole-genome sequencing study of achalasia and identify a recessively inherited frameshift variant in FAM129C (p.Ala454fs). A CRISPR/Cas9-engineered Fam129c-mutant mouse model recapitulating key features of achalasia was established, including growth retardation, elevated lower esophageal sphincter (LES) pressure, and selective loss of inhibitory neurons. Multi-omic analyses revealed substantial B cell expansion and activation within the LES, accompanied by enhanced humoral immune responses. Time-course experiments demonstrated that B cell accumulation preceded overt neuronal loss, while B cell depletion via anti-CD20 antibodies or intravenous immunoglobulin treatment partially rescued the phenotypes. Further protein profiling and cell-based assays suggested that the GABAA receptor may represent one potential neuronal antigen targeted by circulating autoantibodies. Together, these findings identify FAM129C as a genetic contributor to achalasia and support a neuroimmune mechanism in which B cell activation and autoantibody-mediated responses contribute to inhibitory neuronal injury. These results provide important insights into achalasia pathogenesis and highlight the potential of immunomodulatory strategies for disease intervention in the early stage.