GFRA4 is a glycosylphosphatidylinositol-linked receptor for persephin (PSPN), a neurotrophic ligand 1. It functions as the ligand-binding component of a signaling complex with the RET receptor tyrosine kinase, enabling PSPN-induced RET autophosphorylation and activation 1. GFRA4 undergoes developmentally regulated alternative splicing, generating GPI-linked, transmembrane, and putative soluble isoforms with tissue-specific expression patterns 2. The receptor is predominantly expressed in thyroid medullary C cells, parathyroid, and pituitary glands, suggesting roles in endocrine cell development 21. In the enteric nervous system, GFRA4 expression supports neural crest-derived cell survival and proliferation; reduced GFRA4 expression due to aberrant CpG hypermethylation contributes to Hirschsprung disease pathogenesis 3. MicroRNA regulation of GFRA4 (via miR-195-5p and miR-483-5p) modulates enteric nerve cell proliferation and apoptosis in disease contexts 45. GFRA4 expression is also detected in intervertebral disc tissues, where it may participate in discogenic pain pathogenesis 6. Additionally, rare GFRA4 variants show association with paroxysmal atrial fibrillation in Japanese populations 7, suggesting broader cardiovascular involvement.