TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome
Authors: Nils J Lambacher
Lydie Burglen
Christel Thauvin-Robinet
Oliver E Blacque
Diane Doummar
Ange-Line Bruel
Sophie Saunier
Katarzyna Szymańska
Colin A Johnson
Michelle Peckham
Gavin J McManus
Jean-Baptiste Rivière
Tania Attié-Bitach
Teunis J P van Dam
Rachel H Giles
Karl Gaff
Martijn A Huynen
Stefanie Kuhns
Alistair Curd
Julie E Kennedy
Ka Man Wu
Robin van der Lee
Laurence Faivre
Gisela G Slaats
Journal: Nature Cell Biology (2016)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Transition zone; ciliary subcompartment; protein diffusion barrier; TZ defects; ciliopathies
Affiliations: School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland., EA4271 GAD, Genetics of Development Abnormalities, Burgundy University, 21078 Dijon, France., Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA Nijmegen, Netherlands., Section of Ophthalmology and Neurosciences, Leeds Institute of Biomolecular &Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK., Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands., School of Biochemistry and Immunology, Microscopy Facility, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland., Centre de référence des malformations et maladies congénitales du cervelet et Service de Génétique, APHP, Hôpital Trousseau, 75012 Paris, France., INSERM U1141, 75019 Paris, France., FHU TRANSLAD, CHU Dijon, 21079 Dijon, France., INSERM UMR1163, Hôpital Necker-Enfants Malades, 75015 Paris, France., Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France., Institut IMAGINE, 75015 Paris, France., Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France., School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.

Abstract:  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 syndrome (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. 

Retracted: No

PubPeer comments:
 Dr Christel Thauvin-Robinet collected patients with Joubert syndrome and OFD. Cases 1 and 2: ![file] Case 2 is characterized by a retrocerebellar cyst whereas case 1 has no retrocerebellar cyst ![file] The right figure shows a patient with a huge retrocerebellar cyst. This is not case 1 but case 2. This error should be corrected. Furthermore, these two patients were already published (as case of OFD VI) by Dr Thauvin-Robinet ![file] ![file] I am surprised that the authors did not precise this specific point. , 
 These two cases have been republished in J Med Genet 2017;54:371-380. ![file] Case 3a (K) and case 3b (L) , 
 #1 Thank you for pointing out the possible mislabelling of case 1 and 2. I have forwarded this comment to Dr. Thauvin-Robinet, whose lab generated the data. In relation to your second comment about not citing the 2013 study where the two cases were initially described. In Supplementary Figure 3 we do state that Cases 1 and 2 were previously reported, citing ref 40, and state Darmency-Stambouhl et al 2013 in the figure itself (see the legend for Supplementary Figure 3C). However, your point is fair in that we should have cited Darmency-Stambouhl et al (2013) in the main text of the paper but somehow this didn t happen (possibly due to us having to limit the number of main text references for the journal). I hope this helps answer you queries. ,