PUBLICATION
Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes
- Authors
- 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., and Gleeson, J.G.
- ID
- ZDB-PUB-100601-27
- Date
- 2010
- Source
- Nature Genetics 42(7): 619-625 (Journal)
- Registered Authors
- Davis, Erica, Katsanis, Nicholas
- Keywords
- none
- MeSH Terms
-
- Abnormalities, Multiple/genetics*
- Abnormalities, Multiple/pathology
- Amino Acid Sequence
- Animals
- Base Sequence
- Cell Line
- Cilia/pathology*
- Consanguinity
- Embryo, Mammalian/embryology
- Embryo, Mammalian/metabolism
- Gastrulation/genetics
- Gene Expression Regulation, Developmental
- Genetic Predisposition to Disease
- Green Fluorescent Proteins/genetics
- Green Fluorescent Proteins/metabolism
- Humans
- In Situ Hybridization
- Jews/genetics
- Membrane Proteins/genetics*
- Microscopy, Confocal
- Molecular Sequence Data
- Mutation*
- Pedigree
- Polymorphism, Single Nucleotide
- RNA Interference
- Syndrome
- Zebrafish/embryology
- Zebrafish/genetics
- PubMed
- 20512146 Full text @ Nat. Genet.
Citation
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., and Gleeson, J.G. (2010) Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nature Genetics. 42(7):619-625.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping