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

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. Achalasia is a rare condition characterised by inability to swallow. Here, the authors use whole-genome sequencing to identify a FAM129C variant associated with the disease and characterise B cell responses towards the GABA-A receptor in a mouse model expressing that variant.