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 We have identified the genes AHI1, NPHP1, CEP290, ARL13B, and INPP5E as well as several unpublished genes as mutated in patients with JS.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.

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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Morris, Jill A
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Marin-Valencia, Isaac; Novarino, Gaia; Johansen, Anide et al. (2018) A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features. J Med Genet 55:48-54
Ghosh, Shereen G; Becker, Kerstin; Huang, He et al. (2018) Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome. Am J Hum Genet 103:431-439
Breuss, Martin W; Nguyen, An; Song, Qiong et al. (2018) Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome. Am J Hum Genet 103:296-304
Schaffer, Ashleigh E; Breuss, Martin W; Caglayan, Ahmet Okay et al. (2018) Biallelic loss of human CTNNA2, encoding ?N-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration. Nat Genet 50:1093-1101
Makrythanasis, Periklis; Maroofian, Reza; Stray-Pedersen, Asbjørg et al. (2018) Biallelic variants in KIF14 cause intellectual disability with microcephaly. Eur J Hum Genet 26:330-339
Lardelli, Rea M; Schaffer, Ashleigh E; Eggens, Veerle R C et al. (2017) Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat Genet 49:457-464
Marin-Valencia, Isaac; Gerondopoulos, Andreas; Zaki, Maha S et al. (2017) Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia. Am J Hum Genet 101:441-450
Friedman, Jennifer; Feigenbaum, Annette; Chuang, Nathaniel et al. (2017) Pyruvate dehydrogenase complex-E2 deficiency causes paroxysmal exercise-induced dyskinesia. Neurology 89:2297-2298
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
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

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