The transition zone (TZ) ciliary subcompartment is thought to control cilium composition and signalling by facilitating a protein diffusion barrier at the ciliary base. TZ defects cause ciliopathies such as Meckel–Gruber syndrome (MKS), nephronophthisis (NPHP) and Joubert syndrome1 (JBTS). However, the molecular composition and mechanisms underpinning TZ organization and barrier regulation are poorly understood. To uncover candidate TZ genes, we employed bioinformatics (coexpression and co-evolution) and identified TMEM107 as a TZ protein mutated in oral–facial–digital syndrome and JBTS patients. Mechanistic studies in Caenorhabditis elegans showed that TMEM-107 controls ciliary composition and functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking and assembly of membrane to microtubule Y-link connectors. Furthermore, nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237). Finally, MKS module membrane proteins are immobile and super-resolution microscopy in worms and mammalian cells reveals periodic localizations within the TZ. This work expands the MKS module of ciliopathy-causing TZ proteins associated with diffusion barrier formation and provides insight into TZ subdomain architecture.
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This work was financially supported via the European Community’s Seventh Framework Programme FP7/2009 (SYSCILIA grant agreement 241955 to O.E.B., M.A.H., R.H.G. and C.A.J., and Gencodys to M.A.H.), Science Foundation Ireland (11/PI/1037 to O.E.B.), the Dutch Kidney Foundation CP11.18 ‘KOUNCIL’ (to R.H.G.), the GIS-Institut des Maladies Rares (HTS to C.T.-R.), the French Fondation for Rare Disease (to C.T.-R.), the Virgo consortium (FES0908 to M.A.H.), the Netherlands Genomics Initiative (050-060-452, RvdL to M.A.H.), the French Ministry of Health (PHRC national 2010-A01014-35 and 2013 to C.T.-R.), the Fondation pour la Recherche Médicale (DEQ20130326532 to S.S.), the Regional Council of Burgundy (to C.T.-R.), a Sir Jules Thorn Award for Biomedical Research (JTA/09 to C.A.J.), and the UK Medical Research Council (MR/K011154/1 to C.A.J., and MR/K015613/1 to M.P.). We thank the patients and their families for their participation. We also thank the NHLBI GO Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). We thank M. Leroux (Simon Fraser University, Canada), B. Yoder (University of Alabama, USA), the Caenorhabditis elegans Genetics Center (Minnesota, USA), the National Bioresource project (Tokyo, Japan), the International C. elegans gene knockout consortium, and the C. elegans Million Mutation Project for nematode reagents. We are grateful to C. Eggeling and C. Lagerholm (Weatherall Institute of Molecular Medicine and the Wolfson Imaging Center, Oxford, UK) for assistance with STED microscopy, D. Scholz and T. Toivonen (UCD Conway Institute imaging facility, Dublin, IRL) for imaging support, and R. Dijkstra (Scientific Volume Imaging bv, Hilversum, NL) for assistance with STED image deconvolution. We also thank A. Cleasby (Faculty of Biological Sciences, University of Leeds, Leeds, UK) for help with developing the dSTORM technique, B. Chih (Genentech, South San Francisco, CA, USA) for the kind gift of polyclonal anti-TMEM17 and TMEM231 antibodies, and T. McMorrow (University College Dublin, Dublin, Ireland) for the generous gift of the RPTEC/TERT1 cells. We thank D. Rodriguez (Trousseau hospital, Paris) for assistance with analysis of brain MRIs. The dSTORM microscope was generously funded by alumnus M. Beverly, in support of the University of Leeds ‘making a world of difference campaign’.
Integrated supplementary information
Reconstruction derived from a 200 nm section of a C. elegans amphid channel ciliary TZ. Arrow denotes a Y-link density throughout the tomogram, indicating that the Y-link structures are continuous sheets along the axial plane. Bar; 100 nm.