The ciliopathies represent an emerging class of human developmental disorders affecting brain, eye, liver, kidney, digit, skeletal muscle, and lung, all united by disruption of structure or function of the primary cilium. Joubert syndrome (JS) is a ciliopathy, characterized by structural brain anomalies, mental retardation and ataxia, with frequent accompanying retinal blindness, renal failure, polydactyly and hepatic fibrosis. Identifying the pathogenic mechanisms of JS is important for three reasons: 1] A suspicion of a cerebellar disorder frequently leads to pregnancy termination, so understanding these causes can lead to improved predictions about pregnancy outcome. 2] JS has among the highest incidence of co-existent autism among pediatric brain disorders, suggesting what we learn can impact our understanding of more complex disorders. 3] With an improved understanding of basic mechanisms, the field will be in a better position to consider potential treatments. We have identified the genes AHI1, NPHP1, CEP290, ARL13B, and INPP5E as well as several unpublished genes as mutated in patients with JS. We have identified essential signaling functions of these genes in kidney homeostasis, rhodopsin transport, Wnt-, small GTPase-, and phosphatidyl inositol signaling using a combination of mouse modeling, cell biology and biochemical approaches. However, the physiological role of these genes in the pathogenesis of the ciliopathies and the genetic networks remain unknown. The overall goal of this renewal application is to elucidate the developmental, signaling and cell biological mechanisms of the ciliopathy genes underlying the multi- organ involvement in JS, particularly in the context of brain development. We will utilize both traditional and conditional knockout technologies in mouse, genetic modeling in zebrafish, and advanced live-cell imaging capability that will synergize to help advance our understanding of the mechanisms of this important class of disease.

Public Health Relevance

Joubert syndrome is a devastating recessive childhood developmental disorder affecting brain, eye, liver and kidney development, resulting in frequent mental retardation, ataxia, blindness, and renal failure. The underlying causes appear to relate to defects of primary cilia, which are tiny hair-like antennae that extend from most cells. We will study the signaling mechanisms of the genes that others and we have implicated in this disorder in order to understand the basis of these human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052455-06
Application #
8225137
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Riddle, Robert D
Project Start
2007-06-01
Project End
2016-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
6
Fiscal Year
2012
Total Cost
$330,980
Indirect Cost
$112,230
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kim, Ji Hyun; Ki, Soo Mi; Joung, Je-Gun et al. (2016) Genome-wide screen identifies novel machineries required for both ciliogenesis and cell cycle arrest upon serum starvation. Biochim Biophys Acta 1863:1307-18
Rosti, Rasim O; Dikoglu, Esra; Zaki, Maha S et al. (2016) Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene. Am J Med Genet A 170A:992-8
Jerber, Julie; Zaki, Maha S; Al-Aama, Jumana Y et al. (2016) Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly. Am J Hum Genet 99:1181-1189
Li, Hongda; Saucedo-Cuevas, Laura; Regla-Nava, Jose A et al. (2016) Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation. Cell Stem Cell 19:593-598
Li, Hongda; Bielas, Stephanie L; Zaki, Maha S et al. (2016) Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly. Am J Hum Genet 99:501-10
Roosing, Susanne; Romani, Marta; Isrie, Mala et al. (2016) Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes. J Med Genet 53:608-15
Akizu, Naiara; Cantagrel, Vincent; Zaki, Maha S et al. (2015) Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction. Nat Genet 47:528-34
Zaki, M S; Selim, L; Mansour, L et al. (2015) Mutations in FA2H in three Arab families with a clinical spectrum of neurodegeneration and hereditary spastic paraparesis. Clin Genet 88:95-7
Roosing, Susanne; Hofree, Matan; Kim, Sehyun et al. (2015) Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome. Elife 4:e06602
Valente, Enza Maria; Rosti, Rasim O; Gibbs, Elizabeth et al. (2014) Primary cilia in neurodevelopmental disorders. Nat Rev Neurol 10:27-36

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