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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Riddle, Robert D
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University of Washington
Schools of Medicine
United States
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Phelps, Ian G; Dempsey, Jennifer C; Grout, Megan E et al. (2018) Interpreting the clinical significance of combined variants in multiple recessive disease genes: systematic investigation of Joubert syndrome yields little support for oligogenicity. Genet Med 20:223-233
Fleming, Leah R; Doherty, Daniel A; Parisi, Melissa A et al. (2017) Prospective Evaluation of Kidney Disease in Joubert Syndrome. Clin J Am Soc Nephrol 12:1962-1973
Poretti, Andrea; Snow, Joseph; Summers, Angela C et al. (2017) Joubert syndrome: neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause. J Med Genet 54:521-529
Van De Weghe, Julie C; Rusterholz, Tamara D S; Latour, Brooke et al. (2017) Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish. Am J Hum Genet 101:23-36
Aldinger, Kimberly A; Doherty, Dan (2016) The genetics of cerebellar malformations. Semin Fetal Neonatal Med 21:321-32
Slaats, Gisela G; Isabella, Christine R; Kroes, Hester Y et al. (2016) MKS1 regulates ciliary INPP5E levels in Joubert syndrome. J Med Genet 53:62-72
Schueler, Markus; Halbritter, Jan; Phelps, Ian G et al. (2016) Large-scale targeted sequencing comparison highlights extreme genetic heterogeneity in nephronophthisis-related ciliopathies. J Med Genet 53:208-14
Bachmann-Gagescu, R; Dempsey, J C; Phelps, I G et al. (2015) Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. J Med Genet 52:514-22
Bachmann-Gagescu, Ruxandra; Dona, Margo; Hetterschijt, Lisette et al. (2015) The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking. PLoS Genet 11:e1005575
Bachmann-Gagescu, Ruxandra; Phelps, Ian G; Dempsey, Jennifer C et al. (2015) KIAA0586 is Mutated in Joubert Syndrome. Hum Mutat 36:831-5

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