Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes

• Published in: Nature genetics Vol. 42; no. 7; pp. 619 - 625
• Main Authors: Travaglini, Lorena, Shalev, Stavit, Attié-Bitach, Tania, Alkindy, Adila, Sagie, Tally Lerman, Mazzotta, Annalisa, Lee, Ji Eun, Hildebrandt, Friedhelm, Lev, Dorit, Elkhartoufi, Nadia, Michelson, Marina, Inglehearn, Chris, Munnich, Arnold, Thomas, Sophie, Ben-Zeev, Bruria, Russ, Carsten, Dallapiccola, Bruno, Fede, Carmelo, Gleeson, Joseph G, Tolentino, Jerlyn C, Yaron, Yuval, Krause, Amanda, Mougou-Zerelli, Soumaya, Johnson, Colin A, Otto, Edgar A, Silhavy, Jennifer L, Cibulskis, Kristian, Salpietro, Carmelo D, Diplas, Bill H, Davis, Erica E, Sougnez, Carrie, Lee, Jeong Ho, Saad, Ali, Illi, Barbara, Swistun, Dominika, Saunier, Sophie, Boltshauser, Eugen, Vekemans, Michel, Gabriel, Stacey, Szymanska, Katarzyna, Adams, Matthew, Logan, Clare V, Romani, Sveva, Valente, Enza Maria, Brancati, Francesco, Mikula, Mario, Strom, Charles M, Katsanis, Nicholas, Iannicelli, Miriam, Roume, Joelle, Held, Susanne
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2010; Nature Publishing Group
• Subjects: 631/136/2432; 631/208/2489/144; Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Agriculture; Amino Acid Sequence; Amino acids; Animal Genetics and Genomics; Animals; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line; Cilia - pathology; Colleges & universities; Consanguinity; Danio rerio; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Freshwater; Fundamental and applied biological sciences. Psychology; Gastrulation - genetics; Gene Expression Regulation, Developmental; Gene Function; Gene mutations; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Health aspects; Human Genetics; Humans; In Situ Hybridization; Jews - genetics; Joubert syndrome; letter; Malformations of the nervous system; Meckel-Gruber syndrome; Medical sciences; Membrane Proteins - genetics; Microscopy, Confocal; Molecular Sequence Data; Mutation; Neurology; Pedigree; Polymorphism, Single Nucleotide; Proteins; Risk factors; RNA Interference; Syndrome; Zebrafish - embryology; Zebrafish - genetics; France; Italy; United Kingdom; Nervous system diseases; Urinary system disease; Malformation; Diseases of the osteoarticular system; Digestive diseases; Mutation; Meckel syndrome; Genetic disease
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.594

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.