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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290
American Journal of Human Genetics, Volume 83, No. 5, Year 2008
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Description
Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GST pull-down experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies. © 2008 The American Society of Human Genetics.
Authors & Co-Authors
Gorden, Nicholas T.
United States, Seattle
University of Washington School of Medicine
Arts, Heleen H.
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Parisi, Melissa A.
United States, Seattle
University of Washington School of Medicine
Coene, Karlien L.M.
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Letteboer, Stef J.F.
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
van Beersum, Sylvia E.C.
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Mans, Dorus A.
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Hikida, Abigail
United States, Seattle
University of Washington School of Medicine
Eckert, Melissa L.
United States, Davis
University of California, Davis
Knutzen, Dana M.
United States, Seattle
University of Washington School of Medicine
Alswaid, Abdulrahman Faiz
Saudi Arabia, Riyadh
King Abdulaziz Medical City - Riyadh
Özyürek, Hamit
Turkey, Samsun
Ondokuz Mayis Üniversitesi
Dibooǧlu, Sel
United States, St. Louis
University of Missouri-st. Louis
Otto, Edgar A.
United States, Ann Arbor
Michigan Medicine
Liu, Yangfan
United States, Baltimore
Johns Hopkins Medicine
Davis, Erica E.
United States, Baltimore
Johns Hopkins Medicine
Hutter, Carolyn M.
United States, Seattle
University of Washington
Bammler, Theo K.
United States, Seattle
University of Washington
Farin, Federico M.
United States, Seattle
University of Washington
Dorschner, Michael O.
United States, Seattle
University of Washington School of Medicine
Topçu, Meral M.D.
Turkey, Ankara
Hacettepe Üniversitesi
Zackai, Elaine H.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Rosenthal, Philip Jon
United States, San Francisco
University of California, San Francisco
Owens, Kelly N.
United States, Seattle
University of Washington School of Medicine
United States, Seattle
University of Washington
Katsanis, Nicholas
United States, Baltimore
Johns Hopkins Medicine
Vincent, John B.
Canada, Toronto
Centre for Addiction and Mental Health
Hildebrandt, Friedhelm
United States, Ann Arbor
Michigan Medicine
Rubel, Edwin W.
United States, Seattle
University of Washington School of Medicine
United States, Seattle
University of Washington
Raible, David W.
United States, Seattle
University of Washington
Knoers, Nine V.A.M.
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Chance, Phillip F.
United States, Seattle
University of Washington School of Medicine
Roepman, Ronald
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Moens, Cecilia Bernelot
United States, Chevy Chase
Howard Hughes Medical Institute
Glass, Ian A.
United States, Seattle
University of Washington School of Medicine
Doherty, Dan A.
United States, Seattle
University of Washington School of Medicine
Statistics
Citations: 226
Authors: 35
Affiliations: 14
Identifiers
Doi:
10.1016/j.ajhg.2008.10.002
ISSN:
00029297
Research Areas
Cancer
Disability
Genetics And Genomics
Health System And Policy
Noncommunicable Diseases