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Ciliopathies Exome Sequencing Initiative

ABSTRACT:

The study is aimed at identifying new genes involved in pediatric brain disorders from inbred families originating predominantly in the Middle East. Each patient analyzed to date has a specific and highly unique neurodevelopmental disorder that is likely to be recessive in nature. Many patients have one of the diseases along the "ciliopathy" spectrum of diseases, with evidence of kidney failure, retinal blindness and cerebellar ataxia.

PROVIDER: phs000288.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies.

Bielas Stephanie L SL Silhavy Jennifer L JL Brancati Francesco F Kisseleva Marina V MV Al-Gazali Lihadh L Sztriha Laszlo L Bayoumi Riad A RA Zaki Maha S MS Abdel-Aleem Alice A Rosti Rasim Ozgur RO Kayserili Hulya H Swistun Dominika D Scott Lesley C LC Bertini Enrico E Boltshauser Eugen E Fazzi Elisa E Travaglini Lorena L Field Seth J SJ Gayral Stephanie S Jacoby Monique M Schurmans Stephane S Dallapiccola Bruno B Majerus Philip W PW Valente Enza Maria EM Gleeson Joseph G JG

Nature genetics 20090809 9

Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly and is included in the newly emerging group of 'ciliopathies'. In individuals with Joubert disease genetical ...[more]

PMID: 19668216

Publication: 1/3

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Ciliopathies Exome Sequencing Initiative

Project description:<p>The study is aimed at identifying new genes involved in pediatric brain disorders from inbred families originating predominantly in the Middle East. Each patient analyzed to date has a specific and highly unique neurodevelopmental disorder that is likely to be recessive in nature. Many patients have one of the diseases along the "ciliopathy" spectrum of diseases, with evidence of kidney failure, retinal blindness and cerebellar ataxia.</p>

| phs000288 | dbGaP

Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization

2022-10-03 | GSE214213 | GEO

Cerebellar abiotrophy in working Kelpies with a later clinical onset

Project description:Australian working Kelpie dogs are known to be affected with an autosomal recessive form of inherited cerebellar ataxia (cerebellar abiotrophy, CA) that is characterised by a degeneration of Purkinje and granule cells in the cerebellar cortex. The clinical signs of CA include cerebellar ataxia, head tremor, motor in-coordination, wide based stance and high stepping gait, with varied clinical onset age. The clinical and pathological features are similar to cerebellar ataxias in humans. The genome-wide association study on a group of working Kelpies affected with the later onset form of CA identified a region on chromosome 9 to be strongly associated with the disease phenotype. Homozygosity analysis and whole genome sequencing identified a missense single nucleotide polymorphism, that segregated with the CA phenotype.

2022-12-31 | GSE102154 | GEO

Proteomic datasets from sacsin knockout human SH-SY5Y and mouse primary cortical neurons

Project description:Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset cerebellar ataxia caused by mutations in SACS, which encodes the protein sacsin. Cellular ARSACS phenotypes include mitochondrial dysfunction, intermediate filament disorganization, and the progressive death of cerebellar Purkinje neurons. It is unclear how the loss of sacsin function causes these deficits, or why they manifest as cerebellar ataxia. Here, we performed multi-omic profiling in sacsin knockout (KO) cells, and identified alterations in microtubule dynamics, protein trafficking, and mislocalization of synaptic and focal adhesion proteins, including multiple integrins. Focal adhesion structure, signaling, and function were affected in KO cells, which could be rescued by reducing levels of PTEN, an overabundant negative regulator of focal adhesion signaling. Purkinje neurons in ARSACS mice possessed mislocalization of ITGA1, and disorganization of synaptic structures in the deep cerebellar nucleus (DCN). Interactome analysis revealed that sacsin regulates protein-protein interactions between structural and synaptic adhesion proteins. Our findings suggest that disrupted trafficking of synaptic adhesion proteins is a causal molecular deficit underlying ARSACS.

2022-10-25 | PXD036906 | Pride

Evaluation of Therapeutic Potential of Resveratrol-Loaded Nanostructured Lipid Carriers on Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay Patients Fibroblasts

Project description:Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurological disease characterized by autosomal recessive mutations in the sacsin gene (SACS), that cause in patients progressive cerebellar atrophy, damage of the peripheral nerves, and significant retinal changes and cognitive impairment. No effective therapies have been proposed for ARSACS, even if some evidences suggest that powerful antioxidant agents can be considered a therapeutic tool. Resveratrol (Res) is a natural polyphenol compound derived from vegetal sources, the application of which in biomedicine is increasing in the latest years because of its significant therapeutic effects, in particular in neurodegenerative diseases. In this study, we provide evidences about its potential exploitation in the treatment of ARSACS. Because of the low solubility of resveratrol in physiological media, a nanoplatform based on nanostructured lipid carriers is here proposed for its encapsulation and delivery. Resveratrol-loaded nanostructured lipid carriers (Res-NLCs) have been synthetized, characterized, and tested on healthy and ARSACS patient fibroblasts. Nanovectors displayed optimal stability and biocompatibility, and excellent antioxidant and anti-inflammatory activities. A comprehensive investigation at gene (with real-time quantitative RT-PCR (qRT-PCR)) and protein (with proteomics) level demonstrated the therapeutic potential of Res-NLCs, encouraging future investigations on pre-clinical models.

2021-11-03 | PXD025718 | Pride

Sacsin, the ARSACS disease protein, controls lysosomal positioning and reformation by regulating microtubule dynamics

Project description:Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a fatal brain disorder featuring cerebellar neurodegeneration leading to spasticity and ataxia. ARSACS is caused by mutations in the SACS gene that encodes sacsin, a massive 4579 amino acid protein with multiple modular domains. Here we demonstrate that sacsin binds to microtubules and regulates microtubule dynamics. Loss of sacsin function in knockout cell lines, knockdown and knockout neurons, and patient fibroblasts leads to alterations in lysosomal transport, positioning, function and reformation following autophagy.

2022-10-15 | PXD033823 | Pride

Homo sapiens

Project description:Identification of autosomal recessive spastic paraplegia with cerebellar ataxia and neuropathy

| PRJDB2708 | ENA

Comparing the cerebellar transcriptome of Sacs KO versus WT mice

Project description:Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in SACS gene encoding sacsin. ARSACS patients and mouse models display early degeneration of cerebellum in agreement with high sacsin expression in this organ. We performed unbiased transcriptomic of cerebella from Sacs KO mice versus controls to dissect the mechanisms underlying cerebellar degeneration in ARSACS.

2023-08-08 | GSE200876 | GEO

Mutations in GEMIN5 cause a neurodevelopmental ataxia syndrome by a loss-of-1function mechanism

Project description:GEMIN5 is a critical component of snRNP assembly complex. Patients carrying novel autosomal recessive variants in the GEMIN5 gene showed symptoms of developmental delay, central hypotonia, and cerebellar ataxia which are distinct than classical spinal muscular atrophy. We performed RNA-seq analysis in iPSC-derived differentiated neurons with biallelic GEMIN5-H913R mutation to identify global alterations in various genes and pathways mediated by GEMIN5 mutations in patients.

2021-03-11 | GSE168622 | GEO

Project description:Norwegian Buhund Cerebellar Ataxia

| PRJEB35134 | ENA