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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-34764

Valente, E M; Logan, C V; Mougou-Zerelli, S; Lee, J H; Silhavy, J L; Brancati, F; Iannicelli, M; Travaglini, L; Romani, S; Illi, B; Adams, M; Szymanska, K; Mazzotta, A; Lee, J E; Tolentino, J C; Swistun, D; Salpietro, C D; Fede, C; Gabriel, S; Russ, C; Cibulskis, K; Sougnez, C; Hildebrandt, F; Otto, E A; Held, S; Diplas, B H; Davis, E E; Mikula, M; Strom, C M; Ben-Zeev, B; Lev, D; Sagie, T L; Michelson, M; Yaron, Y; Krause, A; Boltshauser, E; Elkhartoufi, N; Roume, J; Shalev, S; Munnich, A; Saunier, S; Inglehearn, C; Saad, A; Alkindy, A; Thomas, S; Vekemans, M; Dallapiccola, B; Katsanis, N; Johnson, C A; Attié-Bitach, T; Gleeson, J G (2010). Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nature Genetics, 42(7):619-625.

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Abstract

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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
DDC:610 Medicine & health
Language:English
Date:2010
Deposited On:15 Jul 2010 08:49
Last Modified:02 Dec 2013 15:31
Publisher:Nature Publishing Group
ISSN:1061-4036
Publisher DOI:10.1038/ng.594
PubMed ID:20512146

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