GJC2 encodes connexin 47 (Cx47), a gap junction protein essential for intercellular communication in the nervous system and lymphatic vasculature. In oligodendrocytes, Cx47 forms homotypic channels with adjacent oligodendrocytes and heterotypic channels with astrocytic Cx43, facilitating both electrical and metabolic coupling 1. GJC2 is temporospatially regulated during early myelination and is expressed in oligodendrocyte precursor cells before CNS myelination begins 2. The protein is critical for proper myelin deposition and maintenance; deficient Cx47 expression or function results in insufficient myelin formation 3. Mutations in GJC2 cause three distinct CNS phenotypes: Pelizaeus-Merzbacher-like disease 1 (PMLD1), spastic paraplegia 44 (SPG44), and subclinical leukodystrophy 1. Pathogenic mutations disrupt channel function through multiple mechanisms—pore-lining α-helix modifications causing channel closure, impaired gap junction plaque formation, or reduced plasma membrane interactions 4. Beyond the CNS, GJC2 mutations cause venous valve defects through disrupted organization of valve-forming endothelial cells 5 and lymphatic malformations via altered lymphatic valve development rather than contraction dyssynchrony 6. These pleiotropic effects reflect Cx47's broad expression across multiple tissue types requiring coordinated intercellular communication.