TMEM107 recruits ciliopathy proteins to anchored periodic subdomains of the ciliary transition zone membrane and is mutated in Joubert syndrome.. TMEM107 in joubert Syndrome

The transition zone (TZ) ciliary subcompartment is thought to control cilium composition and signaling by facilitating a protein diffusion barrier at the ciliary base, and TZ defects associate with ciliopathies such as Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP) and Joubert syndrome (JBTS). However, the molecular composition and mechanisms underpinning TZ organisation and barrier regulation are poorly understood. To uncover candidate TZ genes, we employed bioinformatics (co-expression and co-evolution) and identified TMEM107 as a new TZ protein mutated in oral-facial-digital syndrome (OFD) and JBTS patients. Mechanistic studies in Caenorhabditis elegans showed TMEM107 controls ciliary composition and functions redundantly with NPHP4 to regulate cilium integrity, TZ docking and assembly of membrane to microtubule Y-link connectors. Furthermore, nematode TMEM107 occupies a new intermediate layer of the TZ-localised MKS functional module by organising TZ recruitment of ciliopathy proteins MKS1, TMEM17, TMEM231 and TMEM237. Finally, MKS module membrane proteins are immobile and super resolution microscopy (STED and dSTORM) in worms and mammalian cells reveals periodic localisations within the TZ. This work expands the MKS module of ciliopathy-causing TZ proteins associated with diffusion barrier formation and provides insight into TZ membrane subdomain architecture.