Congenital ataxia presents in early childhood with non-progressive hypotonia, cognitive, gross and fine motor delays. These disorders are distinct from the progressive ataxias because of the presence of congenital cerebellar malformations and recessive modes of inheritance. Joubert Syndrome and Related Disorders (JSRD) constitutes a subset of these conditions, consisting of a cerebella midline (vermis) malformation, and a nearly pathognomonic Molar Tooth sign on brain Imaging (MTI). There is significant phenotypic heterogeneity in JSRD: some patients display the classical form (limited to brain), and others display additionally congenital retinal blindness, progressive kidney failure, cerebral cortical abnormalities or a striking brain wiring phenotype in which each cerebral cortical hemisphere projects output to the ipsilateral side of the body, but receives sensory information from the contralateral side. The cellular and developmental bases of these conditions are not understood. Mutations in two genes, NPHP1 and AHI1, are associated with JSRD. In an exciting new development, we identified the third JSRD gene, CEP290 (submitted). Compelling evidence suggests these proteins function at the cilia/centrosome. Here we propose to apply molecular techniques to study roles of these three genes by performing mutational analyses, genotype-phenotype correlations, test the encoded proteins for a possible role in cilia-based intraflagellar transport, and test animal models for defects in neuronal proliferation and axon guidance. Together this data will provide a framework to understand the role of these genes in the spectrum of conditions seen in JSRD. 1. We will perform comprehensive mutation analysis and genotype-phenotype correlations in a cohort of 180 JSRD probands to test the hypothesis that NPHP1 or CEP290 mutations are associated with JSRD plus kidney failure, whereas AHI1 mutations are associated with JSRD plus cortical abnormalities. 2. We will test the possibility that these genes function at the cilia/centrosome to mediate transduction of Wnt or Sonic Hedgehog signals, using loss- and gain-of-function analyses. 3. We will analyze the brain phenotype of mice with targeted deletions of each gene to test whether these pathways regulate cerebella granule neuron proliferation and axon guidance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052455-04
Application #
7807072
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Gwinn, Katrina
Project Start
2007-06-01
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$338,307
Indirect Cost
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
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
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
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
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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