Screening Cases of Isolated Dystonia and Controls for Variants in CIZ1
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ABSTRACT:
PROVIDER: PRJNA407257 | ENA |
REPOSITORIES: ENA
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Project description:<p>Recently, we have identified that variants in <i>CIZ1</i> gene is associated with dystonia. To identify the prevalence of <i>CIZ1</i> mutations in dystonia population, we use High resolution melting (HRM) to examine all the coding sequence in 3976 subjects with primary dystonia as well as 1819 subjects of normal controls. Indels in Q rich region of exon 2 in <i>CIZ1</i> were identified in 21 subjects with dystonia but only 3 controls (P<0.05). Other single nucleotide change variants were also found in some of the patients which include a novel missense mutation (c.787A>G, p.R263G) found in a female patient with apparently familial dystonia. We confirmed that mutations in <i>CIZ1</i> could be associated with dystonia but in rare cases.</p>
| phs001455 | dbGaP
Project description:Screening Cases of Isolated Dystonia and Controls for Variants in CIZ1
| PRJNA407258 | ENA
Project description:Ciz1 promotes initiation of mammalian DNA replication and is present within nuclear matrix associated DNA replication factories. Depletion of Ciz1 from normal and cancer cells restrains entry to S phase and inhibits cell proliferation. Several alternative splicing events with putative functional consequences have been identified and reported, but many more variants are predicted to exist based on publicly available mRNAs and expressed sequence tags. Here we report the development and validation of a custom exon and exon-junction microarray focused on the human Ciz1 gene, capable of reproducible detection of differential splice-variant expression. Using a pair of paediatric cancer cell lines and a pool of eight normal lines as reference, the array identified expected and novel Ciz1 splicing events. One novel variant (delta 8-12) that encodes a predicted protein lacking key functional sites, was validated by quantitative RT-PCR and found to be over-represented in a range of other cancer cell lines, and over half of a panel of primary lung tumours.
2009-11-01 | E-MEXP-2331 | biostudies-arrayexpress
Project description:Gene expression studies were performed to identify pathways possibly dysregulated by mutant in the gene GM-NM-1(olf). These experiments employed RNA derived from lymphoblastoid cell lines established for 4 affected carriers and 4 non-carriers. In comparison to endogenous control and other dystonia-associated genes, GNAL was expressed at relatively low levels in lymphoblastoid cell lines. Comparison of whole blood expression profiles of mutation carrying dystonia patients with normal controls
2013-01-26 | E-GEOD-43771 | biostudies-arrayexpress
Project description:Spinal interneurons are critical modulators of locomotor circuit function. In the dorsal spinal cord, a set of interneurons called GABApre presynaptically inhibits proprioceptive sensory afferent terminals, thus negatively regulating sensory-motor signaling. While deficits in presynaptic inhibition have been inferred in human locomotor diseases, including dystonia, it remains unknown whether GABApre circuit components are altered in these conditions. In this study, we use developmental timing to show that GABApre neurons are a late Ptf1a-expressing subclass and localize to the intermediate spinal cord. Using a microarray screen to identify genes expressed in this intermediate population, we find the kelch-like family member Klhl14, implicated in dystonia through its direct binding with torsion-dystonia related protein Tor1a. Furthermore, in Tor1a mutant mice in which Klhl14 and Tor1a binding is disrupted (Dyt1ΔE), GABApre-sensory afferent synapse formation is impaired. Our findings suggest a potential contribution of GABApre neurons to the deficits in presynaptic inhibition observed in dystonia.
2017-06-03 | GSE99590 | GEO
Project description:<p>Primary torsin dystonias (PTD) are a group of movement disorders characterized by twisting muscle contractures, where dystonia is the only clinical sign (except for tremor) and there is no evidence of neuronal degeneration or an acquired cause. Eleven genes have been mapped for primary dystonia including DYT1 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=1861" target="_blank">TOR1A</a>), <a href="https://www.ncbi.nlm.nih.gov/gene/1862" target="_blank">DYT2</a>, DYT4 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=10382" target="_blank">TUBB4A</a>), DYT6 (<a href="https://www.ncbi.nlm.nih.gov/gene/55145" target="_blank">THAP1</a>), <a href="https://www.ncbi.nlm.nih.gov/gene/?term=1866" target="_blank">DYT7</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=93983" target="_blank">DYT13</a>,, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=100216344" target="_blank">DYT17</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=100885773" target="_blank">DYT21</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=25792" target="_blank">CIZ1</a>, DYT24 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=63982" target="_blank">ANO3</a>), and DYT25 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=2774" target="_blank">GNAL</a>); however, only 3 genes (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=1861" target="_blank">TOR1A</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/55145" target="_blank">THAP1</a>, and <a href="https://www.ncbi.nlm.nih.gov/gene/?term=2774" target="_blank">GNAL</a>) have mutations in early onset dystonia patients. Each is inherited as an autosomal dominant trait but with reduced penetrance, meaning that individuals can carry the mutation but do not show clinical symptoms.</p> <p>The most common form of PTD is adult onset focal accounting for about 90% of all cases of dystonia with a prevalence estimated at 30/100,000 in the general population. A small percentage of focal cases are due to mutations in <a href="https://www.ncbi.nlm.nih.gov/gene/?term=25792" target="_blank">CIZ1</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=63982" target="_blank">ANO3</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/55145" target="_blank">THAP1</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=10382" target="_blank">TUBB4A</a>, and <a href="https://www.ncbi.nlm.nih.gov/gene/?term=2774" target="_blank">GNAL</a>, but the vast majority is unaccounted for and is most likely multigenic or multifactorial. In this grant, focusing on early onset PTD, we will uncover genes that influence the penetrance of DYT1 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=1861" target="_blank">TOR1A</a>) dystonia through GWAS and exome sequencing studies. We will identify other genes for early onset PTD using exome sequencing and determine whether variants within the identified early onset PTD genes or the pathways associated with these genes contribute to susceptibility in the most prevalent form of PTD, focal dystonia, using a case:control association study. The proposed research will identify novel PTD risk factors and genes, which in turn should reveal shared and intersecting pathways leading to a better understanding of the molecular basis of PTD and provide the underpinnings for developing new treatments. Additionally, insight into the factors that modulate disease penetrance would be a first step in determine whether these could be modified leading to a reduced incidence of the disease. </p>
| phs001733 | dbGaP
Project description:DYT1 dystonia is an autosomal-dominantly inherited movement disorder, which is usually caused by a GAG deletion in the TOR1A gene. Due to the reduced penetrance of ~30-40%, the determination of the mutation in a subject is of limited use with regard to actual manifestation of symptoms. In the present study, we used Affymetrix oligonucleotide microarrays to analyze global gene expression in blood samples of 15 manifesting and 15 non-manifesting mutation carriers in order to identify a susceptibility profile beyond the GAG deletion which is associated with the manifestation of symptoms in DYT1 dystonia.We identified a genetic signature which distinguished between asymptomatic mutation carriers and symptomatic DYT1 patients with 86.7% sensitivity and 100% specificity. This genetic signature could correctly predict the disease state in an independent test set with a sensitivity of 87.5% and a specificity of 85.7%.Conclusively, this genetic signature might provide a possibility to distinguish DYT1 patients from asymptomatic mutation carriers. Comparison of whole blood expression profiles of patients with DYT1 dystonia with non manifesting mutation carriers and non mutation carriers
2010-05-26 | E-GEOD-19419 | biostudies-arrayexpress
Project description:Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum ranging from hereditary generalized dystonia with whispering dysphonia (DYT4) to the leukodystrophy hypomyelination syndrome with atrophy of the basal ganglia and cerebellum (H-ABC). To test for the contribution of TUBB4A mutations in different ethnicities (Spanish, Italian, Korean, Japanese), we screened 492 isolated dystonia cases for mutations in this gene and for the first time determined TUBB4A copy number variations in 336 dystonia patients. A potentially pathogenic rare 3bp-in-frame deletion was found in a patient with cervical dystonia but no copy number variations were detected in this study, suggesting that TUBB4A mutations exceedingly rarely contribute to the etiology of isolated dystonia.
| S-EPMC5769152 | biostudies-other
Project description:Dystonia is characterized by involuntary muscle contractions. Its many forms are genetically, phenotypically and etiologically diverse and it is unknown whether their pathogenesis converges on shared pathways. Mutations in THAP1, a zinc-finger transcription factor, cause DYT6, but its neuronal targets and functions are unknown. We used RNA-Seq to assay the in vivo effect of a heterozygote Thap1C54Y or Exon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum. Enriched pathways and gene ontology terms include eIF2α Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Signaling, and Synaptic Long Term Depression pathways, which are dysregulated in a genotype and tissue-dependent manner. Electrophysiological and neurite outgrowth assays confirmed the functional significance of those findings. Notably, several of these pathways were recently implicated in other forms of inherited dystonia, including DYT1. We conclude that dysfunction of these pathways may represent a point of convergence on the pathogenesis of unrelated forms of inherited dystonia.
2017-11-11 | GSE98839 | GEO