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

• DOI: 10.1038/ng.594
• Publication Date: 2010-05-30T19:43:27Z
• Authors: Enza Maria Valente; Clare V Logan; Soumaya Mougou-Ze...; Jeong Ho Lee; Jennifer L Silhavy; Francesco Brancati; Miriam Iannicelli; Lorena Travaglini; Sveva Romani; Barbara Illi; Matthew Adams; Katarzyna Szymanska; Annalisa Mazzotta; Ji Eun Lee; Jerlyn C Tolentino; Dominika Swistun; Carmelo D Salpietro; Carmelo Fede; Stacey Gabriel; Carsten Russ; Kristian Cibulskis; Carrie Sougnez; Friedhelm Hildebr...; Edgar A Otto; Susanne Held; Bill H Diplas; Erica E Davis; Mario Mikula; Charles M Strom; Bruria Ben-Zeev; Dorit Lev; Tally Lerman Sagie; Marina Michelson; Yuval Yaron; Amanda Krause; Eugen Boltshauser; Nadia Elkhartoufi; Joelle Roume; Stavit Shalev; Arnold Munnich; Sophie Saunier; Chris Inglehearn; Ali Saad; Adila Alkindy; Sophie Thomas; Michel Vekemans; Bruno Dallapiccola; Nicholas Katsanis; Colin A Johnson; Tania Attié-Bitach; Joseph G Gleeson
• Keywords: 570; Green Fluorescent Proteins; Molecular Sequence Data; 610; 610 Medicine & health; Article; Cell Line; Consanguinity; 1311 Genetics; Animals; Humans; Abnormalities, Multiple; Genetic Predisposition to Disease; Amino Acid Sequence; Cilia; In Situ Hybridization; Microscopy, Confocal; Base Sequence; Gastrulation; Gene Expression Regulation, Developmental; Membrane Proteins; BARDET BIEDL SYNDROME; PLANAR CELL POLARITY; GRUBER SYNDROME; ACTIN CYTOSKELETON RENAL SYNDROME; GENE; PROTEINS; CILIARY; DISSECTION; MECHANISMS; Embryo, Mammalian; Pedigree; 10036 Medical Clinic; Jews; Mutation

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.