Joubert syndrome (JBTS), related disorders (JSRDs) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n = 10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.
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Lancaster, M.A. & Gleeson, J.G. The primary cilium as a cellular signaling center: lessons from disease. Curr. Opin. Genet. Dev. 19, 220–229 (2009).
Keeler, L.C. et al. Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12-q13.3. Am. J. Hum. Genet. 73, 656–662 (2003).
Valente, E.M. et al. Description, nomenclature, and mapping of a novel cerebello-renal syndrome with the molar tooth malformation. Am. J. Hum. Genet. 73, 663–670 (2003).
Valente, E.M. et al. Distinguishing the four genetic causes of Joubert syndrome-related disorders. Ann. Neurol. 57, 513–519 (2005).
Baala, L. et al. The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am. J. Hum. Genet. 80, 186–194 (2007).
Baala, L. et al. Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. Am. J. Hum. Genet. 81, 170–179 (2007).
Delous, M. et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat. Genet. 39, 875–881 (2007).
Mougou-Zerelli, S. et al. CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation. Hum. Mutat. 30, 1574–1582 (2009).
Roume, J. et al. A gene for Meckel syndrome maps to chromosome 11q13. Am. J. Hum. Genet. 63, 1095–1101 (1998).
Gherman, A., Davis, E.E. & Katsanis, N. The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat. Genet. 38, 961–962 (2006).
Inglis, P.N., Boroevich, K.A. & Leroux, M.R. Piecing together a ciliome. Trends Genet. 22, 491–500 (2006).
Hubner, K., Windoffer, R., Hutter, H. & Leube, R.E. Tetraspan vesicle membrane proteins: synthesis, subcellular localization, and functional properties. Int. Rev. Cytol. 214, 103–159 (2002).
Junge, H.J. et al. TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4/β-catenin signaling. Cell 139, 299–311 (2009).
Caplan, M.J., Kamsteeg, E.J. & Duffield, A. Tetraspan proteins: regulators of renal structure and function. Curr. Opin. Nephrol. Hypertens. 16, 353–358 (2007).
Smith, U.M. et al. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat. Genet. 38, 191–196 (2006).
Edvardson, S. et al. Joubert syndrome (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation. Am. J. Hum. Genet. 86, 93–97 (2010).
Váradi, V., Szabo, L. & Papp, Z. Syndrome of polydactyly, cleft lip/palate or lingual lump, and psychomotor retardation in endogamic gypsies. J. Med. Genet. 17, 119–122 (1980).
Dawe, H.R. et al. The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum. Mol. Genet. 16, 173–186 (2007).
Wallingford, J.B. et al. Dishevelled controls cell polarity during Xenopus gastrulation. Nature 405, 81–85 (2000).
Park, T.J., Haigo, S.L. & Wallingford, J.B. Ciliogenesis defects in embryos lacking inturned or fuzzy function are associated with failure of planar cell polarity and Hedgehog signaling. Nat. Genet. 38, 303–311 (2006).
Veeman, M.T., Axelrod, J.D. & Moon, R.T. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev. Cell 5, 367–377 (2003).
Winter, C.G. et al. Drosophila Rho-associated kinase (Drok) links Frizzled-mediated planar cell polarity signaling to the actin cytoskeleton. Cell 105, 81–91 (2001).
Dawe, H.R. et al. Nesprin-2 interacts with meckelin and mediates ciliogenesis via remodelling of the actin cytoskeleton. J. Cell Sci. 122, 2716–2726 (2009).
Pan, J., You, Y., Huang, T. & Brody, S.L. RhoA-mediated apical actin enrichment is required for ciliogenesis and promoted by Foxj1. J. Cell Sci. 120, 1868–1876 (2007).
Park, T.J., Mitchell, B.J., Abitua, P.B., Kintner, C. & Wallingford, J.B. Dishevelled controls apical docking and planar polarization of basal bodies in ciliated epithelial cells. Nat. Genet. 40, 871–879 (2008).
Lang, P. et al. Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes. EMBO J. 15, 510–519 (1996).
Dutcher, S.K. Elucidation of basal body and centriole functions in Chlamydomonas reinhardtii. Traffic 4, 443–451 (2003).
Corbit, K.C. et al. Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat. Cell Biol. 10, 70–76 (2008).
Leitch, C.C. et al. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat. Genet. 40, 443–448 (2008).
Badano, J.L. et al. Dissection of epistasis in oligogenic Bardet-Biedl syndrome. Nature 439, 326–330 (2006).
Wittwer, C.T. High-resolution DNA melting analysis: advancements and limitations. Hum. Mutat. 30, 857–859 (2009).
Budde, B.S. et al. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat. Genet. 40, 1113–1118 (2008).
Wolff, A. et al. Distribution of glutamylated α and β-tubulin in mouse tissues using a specific monoclonal antibody, GT335. Eur. J. Cell Biol. 59, 425–432 (1992).
Lancaster, M.A. et al. Impaired Wnt-β-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy. Nat. Med. 15, 1046–1054 (2009).
Johnson, C.A., Padget, K., Austin, C.A. & Turner, B.M. Deacetylase activity associates with topoisomerase II and is necessary for etoposide-induced apoptosis. J. Biol. Chem. 276, 4539–4542 (2001).
Trueba, S.S. et al. PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations. J. Clin. Endocrinol. Metab. 90, 455–462 (2005).
We thank Marshfield Clinic Research Foundation, Center for Inherited Disease Research (supported by the US National Institutes of Health National Heart, Lung, and Blood Institute) for genotyping support and A. Felsenfeld and the Medical Sequencing Initiative at the National Human Genome Research Institute. We acknowledge support for sequencing from the Broad Institute and the Broad Sequencing Platform and J. Meerloo at the University of California, San Diego Neurosciences Microscopy Core (Supported by National Institute of Neurological Disorders and Stroke grant P30NS047101). For patient referrals, we thank C. Jalas at Bonei Olam Center for Rare Jewish Genetic Disorders; M.R. Eccles at the University of Otago; H.M. Harville at University of Michigan; G. Tortorella, S. Briuglia, R. Chimenz, R. Gallizzi and M. Briguglio at University of Messina; E. Bertini and the International JSRD Study Group; and the French Society of Foetal Pathology. We thank E. Morrison, P. Novick and S. Ferro-Novick for helpful discussions; C. Janke (Macromolecular Biochemistry Research Center) for GT335 antibody; P. Robinson (University of Leeds) for siRNA duplexes against Hhari; E. Genin for linkage analysis, S. Audolent, C. Babarit, F. Legendre and H.-M. Gaudé for technical help and O. Duc for confocal microscopy. S.M.-Z. is supported by INSERM-DGRSRT (CS/RN/2008 no. 87). This work was supported by the Italian Ministry of Health (RC2010, Ricerca Finalizzata 2006), Telethon Foundation Italy (GGP08145 to E.M.V.), Pierfranco and Luisa Mariani Foundation (E.M.V.), American Heart Association grant O9POST2250641 (J.E.L.), BDF Newlife, the Medical Research Council (G0700073) and the Sir Jules Thorn Charitable Trust (09/JTA to C.A.J.), l'Agence National pour la Recherche (ANR 07-MRAR-Fetalciliopathies to T.A.-B.), the US National Institutes of Health (R01 DK068306 to F.H.; R01 DK072301, R01 HD04260 and R01 DK075972 to N.K.; National Research Service Award fellowship F32 DK079541 to E.E.D., R01 NS052455 and R01 NS04843 to J.G.G.), Burroughs Wellcome Fund and Howard Hughes Medical Institute (F.H. and J.G.G.).
The authors declare no competing financial interests.
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