Joubert Syndrome and related disorders (JSRD) are a group of autosomal recessive conditions characterized by a distinctive hindbrain malformation (the "molar tooth sign" - MTS) combined with intellectual disability (mental retardation), hypotonia, ataxia, and variably, cystic renal disease, retinal dystrophy and hepatic fibrosis. The overall context of the project is to explore the role of the primary cilium/basal body (PC/BB) in the development/function of the brain and retina. Specifically, we propose to study the molecular function of CC2D2A, a newly discovered gene responsible for JS, and to identify additional components of the genetic/protein network underlying JSRD using several highly informative families.
In Aim 1, we will investigate CC2D2A function by determining temporal, spatial and subcellular expression as well as identifying additional proteins that interact with CC2D2A.
In Aim 2, we will use the cc2d2a photoreceptor phenotype in zebrafish to dissect the molecular function of Cc2d2a and model oligogenic inheritance by examining the effects of JSRD gene mutants/morphant combinations. Given that <50% of JSRD patients have mutations in the known genes, the goal of Aim 3 is to identify additional components of the genetic/protein network responsible for JSRD. This work has broad implications for human disease. Most specifically, it will enhance our understanding of the development/function of the brain, retina and kidney, provide improved diagnostic and prognostic information for patients with JSRD and potentially identify molecular targets for therapies to prevent or delay the progressive retinal, kidney and liver disease seen in JSRD and other ciliopathies. Given the protean role of the PC/BB in cellular function and Mendelian diseases, combined with the emerging associations between PC/BB genes and more common neurological diseases such as schizophrenia and autism, this work is also likely to reveal mechanisms underlying common diseases of the brain, retina, kidney and other tissues.

Public Health Relevance

Joubert syndrome and related disorders (JSRD) provide a model for studying intellectual disability, ataxic cerebral palsy, retinal dystrophy, cystic kidney disease and liver fibrosis. The genes responsible for JSRD have also been implicated in autism, schizophrenia, blindness and obesity. This research will directly benefit individuals with JSRD and their families through improved diagnostic, prognostic and recurrence risk information, as well as monitoring and early treatment for medical complications. Greater understanding of the development/function of the brain, retina, kidney and liver through the study of this relatively rare disorder will facilitate the prevention and treatment of more common disorders of these organ systems and benefit society as a whole.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS064077-05
Application #
8696890
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Riddle, Robert D
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Stratigopoulos, George; Martin Carli, Jayne F; O'Day, Diana R et al. (2014) Hypomorphism for RPGRIP1L, a ciliary gene vicinal to the FTO locus, causes increased adiposity in mice. Cell Metab 19:767-79
Tuz, Karina; Bachmann-Gagescu, Ruxandra; O'Day, Diana R et al. (2014) Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Am J Hum Genet 94:62-72
Halbritter, Jan; Bizet, Albane A; Schmidts, Miriam et al. (2013) Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans. Am J Hum Genet 93:915-25
Tuz, Karina; Hsiao, Yi-Chun; Juarez, Oscar et al. (2013) The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions. J Biol Chem 288:13676-94
Bachmann-Gagescu, Ruxandra; Ishak, Gisele E; Dempsey, Jennifer C et al. (2012) Genotype-phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures. J Med Genet 49:126-37
Lee, Ji Eun; Silhavy, Jennifer L; Zaki, Maha S et al. (2012) CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nat Genet 44:193-9
Sang, Liyun; Miller, Julie J; Corbit, Kevin C et al. (2011) Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145:513-28
Bachmann-Gagescu, Ruxandra; Phelps, Ian G; Stearns, George et al. (2011) The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking. Hum Mol Genet 20:4041-55
Huang, Lijia; Szymanska, Katarzyna; Jensen, Victor L et al. (2011) TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. Am J Hum Genet 89:713-30