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

Abstract

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 GABA_A 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.