TMEM216 is a ciliary transition zone tetraspan transmembrane protein essential for primary ciliogenesis and photoreceptor outer segment integrity. 1 TMEM216 localizes to the ciliary base and forms a complex with Meckelin, with loss-of-function mutations causing defective ciliogenesis and centrosomal docking. 1 In photoreceptors, TMEM216 is critical for normal outer segment disc morphogenesis and protein localization; tmem216 knockout zebrafish exhibit mislocalized rhodopsin and cone opsins, shortened ciliary axonemes, and abnormal disc structures leading to photoreceptor degeneration. 2 Reduced TMEM216 expression from non-coding promoter variants causes non-syndromic retinitis pigmentosa with progressive photoreceptor loss. 3 TMEM216 mutations cause syndromic ciliopathies including Joubert syndrome, Meckel syndrome, and related disorders characterized by neurological and renal manifestations. 1 4 Functionally, TMEM216 perturbations result in hyperactivation of RhoA and Dishevelled signaling and defective ciliogenesis. 1 TMEM216 variants have also been identified in unilateral polymicrogyria, suggesting broader developmental roles. 5 The protein's role in ciliary structure and signaling underlies its pleiotropic disease associations affecting sensory organs, kidney, and brain development.