AnatomyOrganismsDiseasesChemicals and DrugsAnalytical, Diagnostic and Therapeutic Techniques and EquipmentPsychiatry and PsychologyPhenomena and ProcessesInformation ScienceHealth Care
DNA Repeat ExpansionFrontotemporal DementiaAmyotrophic Lateral SclerosisTrinucleotide Repeat ExpansionFrontotemporal Lobar DegenerationRepetitive Sequences, Nucleic AcidTrinucleotide RepeatsProteinsAge of OnsetChromosomes, Human, Pair 9Base SequenceTandem Repeat SequencesPedigreeMolecular Sequence DataDNAMyotonic DystrophyFriedreich AtaxiaNucleic Acid ConformationTelomereSpinocerebellar DegenerationsMicrosatellite RepeatsSpinocerebellar AtaxiasFragile X SyndromeDNA-Binding ProteinsHuntington DiseaseMinisatellite RepeatsMutationFragile X Mental Retardation ProteinPolymerase Chain ReactionPoly ARepetitive Sequences, Amino AcidInverted Repeat SequencesAmino Acid SequenceRahnellaMotor Neuron DiseaseExomeMotor NeuronsSuperoxide DismutaseRNA-Binding Protein FUS
GGGGCCMutationCausativeAmyotrophicProteinsChromosomeGeneticSOD1IntronVariantsAbnormalProteinTrinucleotide2019Designed to detectAddition to genesPhenotypeRisk genes1,600SequenceIdentifyingMutations in the geneMethylationLociDetectPrevalent causeCausalTermed G-quadruplexesPathogenesisFamilialImperfectGenomeOligogenicHumansMotor neuronsNucleotidesMotifsSporadicSequencesOntologyUnclearRs3849942PathwaysVariantMRNAMechanismUnusualAlleleResearchersPromoterCellularSingle gene
GGGGCC10
  • Large expansions of a non-coding GGGGCC-repeat in the first intron of the C9orf72 gene are a common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). (nature.com)
  • Large expansions of the non-coding GGGGCC-repeat in the first intron of the C9orf72 gene have been recently demonstrated to cause ALS and FTD 5 , 6 . (nature.com)
  • The introns containing these large expansions are transcribed and indeed in patients the GGGGCC-repeat expansion is detectable by in situ hybridization in nuclear RNA foci 5 . (nature.com)
  • The GGGGCC expansion of C9orf72 forms runs of adjacent G-repeats and raises the possibility these could form G-quadruplexes. (nature.com)
  • GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the first intron of the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). (qxmd.com)
  • 2011) identified a polymorphic hexanucleotide repeat (GGGGCC) located between the noncoding exons 1a and 1b of the C9ORF72 gene. (coriell.org)
  • Overall, 75 (10.4%) of 722 unrelated patients with FTD, ALS, or both were found to carry an expanded GGGGCC repeat, and DeJesus-Hernandez et al. (coriell.org)
  • However, protein levels of these variants were similar to controls, and analysis of patient frontal cortex and spinal cord tissue showed that the transcribed expanded GGGGCC repeat formed nuclear RNA foci, suggesting a gain-of-function mechanism. (coriell.org)
  • 2011) identified the GGGGCC expanded repeat as a cause of FTD/ALS in families reported by Pearson et al. (coriell.org)
  • A polymerase chain reaction-based assay is utilized to detect C9orf72 GGGGCC hexanucleotide repeat expansions. (mayocliniclabs.com)
Mutation11
  • Researchers found that a mutation on a single gene, C9ORF72 on the short arm of chromosome 9, accounts for nearly 50 percent of the directly inherited, familial ALS and FTD in the Finnish population, and more than a third of familial ALS in other groups of European ancestry. (nih.gov)
  • The mutation, called a hexanucleotide repeat expansion, is an unusual one that involves repeating a DNA sequence over and over again. (nih.gov)
  • By collecting virtually every case within the Finnish population, Traynor and colleagues were able to definitively show that this particular gene mutation plays a role in ALS development-a discovery relevant not just to that population, but critical to our basic understanding of the disorder," said NINDS Director Story Landis, Ph.D. (nih.gov)
  • To date, a number of mutated genes have been identified as playing a role in the development of familial FTD and ALS, but not to the level of significance as the discovery of the 9p21 gene mutation. (nih.gov)
  • Using a transgenic mouse model in which an ALS-like mutation was introduced in the mouse Fus gene, we could show that ALS pathology starts at the neuromuscular juction (the transition between motor nerves and skeletal muscle cells), long before motor neuron cell bodies in the spinal cord degenerate. (europa.eu)
  • Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. (nih.gov)
  • Single-nucleotide polymorphism rs3849942 is associated with ALS, tagging a hexanucleotide repeat mutation in the C9orf72 gene. (ox.ac.uk)
  • DNA from patients with ALS was therefore tested for the mutation. (ox.ac.uk)
  • These results indicate residual association at the C9orf72 locus suggesting a second disease-causing repeat mutation. (ox.ac.uk)
  • The studies, which appear in Nature Neuroscience and PNAS , provide a new layer of detail about how hexanucleotide repeat expansions in the C9ORF72 gene, the most common genetic mutation responsible for both ALS and FTD, causes neuron cell death. (lifeboat.com)
  • Worldwide, approximately 20% of cases of familial ALS are due to a mutation in the Cu/Zn superoxide dismutase-1 gene ( SOD1 ). (medscape.com)
Causative3
  • Genetically, HSPs are classified by the mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and are subdivided by chromosomal locus or causative gene. (medscape.com)
  • To date, more than 20 causative genes have been identified in hereditary ALS. (biomedcentral.com)
  • In addition, about 30 potential causative or disease-modifying genes have also been identified. (biomedcentral.com)
Amyotrophic10
Proteins10
  • The secondary structure of the hexanucleotide repeat is very likely to be involved in determining the proteins it interacts with. (nature.com)
  • Translation of these hexanucleotide repeat sequences gives rise to dipeptide-repeat proteins, which form intracellular protein aggregates in neuronal and non-neuronal cells of affected patients. (europa.eu)
  • This paper reports that certain of these dipeptide repeat proteins interfere with protein synthesis in affected cells, and this molecular derailment may contribute to motor neuron degenetion in C9orf72-ALS patients. (europa.eu)
  • Among the five dipeptide repeat proteins translated from G4C2 HRE, arginine-rich poly-PR (proline:arginine) is extremely toxic. (qxmd.com)
  • These proteins may be important for controlling gene activity or protein production. (medlineplus.gov)
  • The MIR1292 gene provides instructions for making a type of RNA that regulates the activity (expression) of genes that produce proteins called glutamate receptors. (medlineplus.gov)
  • Repeat-associated non-AUG translation of this expansion produces dipeptide repeat proteins (DRPs). (frontiersin.org)
  • This enabled the diversified complementarity and secondary structures that allow RNA species to specifically interact with other components of the cellular machinery such as DNA and proteins. (pharmaceuticalintelligence.com)
  • Alternative splicing of MAPT pre-mRNA generates six major tau isoforms in the adult central nervous system resulting in tau proteins with three or four microtubule-binding repeat domains. (biomedcentral.com)
  • DNA Modulates the Interaction of Genetically Engineered DNA-Binding Proteins and Gold Nanoparticles: Diagnosis of High-Risk HPV Infection. (sinica.edu.tw)
Chromosome3
  • Pur-alpha is a protein that in humans is encoded by the PURA gene located at chromosome 5, band q31. (wikipedia.org)
  • A visual fluorescence analysis of chromosomes from MDS patients shows that deletions of PURA at 5q31 are more strongly linked to progression of MDS to AML when combined with deletions of the PURB gene, including complete loss of chromosome 7. (wikipedia.org)
  • Until now, the gene alteration responsible for the chromosome 9p-linked inherited forms of these diseases remained elusive," said Traynor. (nih.gov)
Genetic10
  • Studies of genetic inactivation of PURA in the mouse provided evidence leading to that for PURA gene disorders in brain disease. (wikipedia.org)
  • NIA and NINDS also funded work by a team from the Mayo Clinic in Florida, reported by Mayo investigator Rosa Rademakers, Ph.D., and colleagues, which independently identified the same repeat DNA sequence as a genetic cause of FTD/ALS. (nih.gov)
  • Identifying this defective gene common to both the inherited forms of ALS and FTD and the sporadic form of ALS provides important new insights into the development of these neurodegenerative diseases," said NIA Director Richard J. Hodes, M.D. "We still have much to learn about the complex interplay between genetic risk for a disorder and the other factors that determine disease onset and progression. (nih.gov)
  • With the plethora of new genes being identified, genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia (SCA), hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth disease (CMT) has become widely accepted. (biomedcentral.com)
  • Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms, translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies, and ultimately finding disease-modifying therapies for neurodegenerative disorders. (biomedcentral.com)
  • Large sample sizes are needed to detect significant associations due to testing of ~ 20,000 genes and because the multiple testing burden is often increased by considering different genetic models. (biomedcentral.com)
  • A hexanucleotide repeat expansion in the non-coding region of the C9ORF72 gene is the largest genetic factor associated with FTD and ALS. (edu.au)
  • The C9orf72 hexanucleotide repeat expansion presents a challenge for testing laboratories and genetic counseling. (cdc.gov)
  • Background Several studies suggest that multiple rare genetic variants in genes causing monogenic forms of neurodegenerative disorders interact synergistically to increase disease risk or reduce the age of onset, but these studies have not been validated in large sporadic case series. (bmj.com)
  • Genetic variation in over 50 genes contributes to the risk of developing neurodegenerative diseases. (bmj.com)
SOD12
  • While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans. (biomedcentral.com)
  • The largest study to date, comprising 2874 cases and 6405 controls of European ancestry, identified the known ALS gene SOD1 as the only gene passing the multiple-testing corrected threshold for significance of association [ 9 ]. (biomedcentral.com)
Intron2
  • The NOP56 gene mutations that cause SCA36 involve a string of six DNA building blocks (nucleotides) located in an area of the gene known as intron 1. (medlineplus.gov)
  • The expanded repeat is located in the promoter region of C9ORF72 transcript variant 1 and in intron 1 of transcript variants 2 and 3. (coriell.org)
Variants6
  • The advent of next generation sequencing (NGS) has allowed for a system-wide, unbiased approach to identify all gene variants in the genome simultaneously. (biomedcentral.com)
  • We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5 × 10 -5 in reference databases. (biomedcentral.com)
  • Whole-exome sequencing (WES) studies designed to identify genes enriched for rare variants have been conducted for ALS. (biomedcentral.com)
  • Association testing has typically been conducted at the gene level comparing the burden of rare coding variants in cases vs controls. (biomedcentral.com)
  • Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. (mayocliniclabs.com)
  • A variety of chemical modifications decorate the nucleic acids, increasing the alphabet of DNA to about a dozen known nucleotide variants. (pharmaceuticalintelligence.com)
Abnormal1
  • Once the abnormal gene products are better understood, specific medical treatments may emerge. (medscape.com)
Protein11
  • Pur-alpha is an ancient, multi-functional DNA- and RNA-binding protein. (wikipedia.org)
  • Following the identification of a Pur factor, which specifically bound a purine-rich sequence in the control region of the c-MYC gene, the gene, PURA, encoding the protein, Pur-alpha, was cloned and sequenced for both human and mouse (GenBank U02098.1). (wikipedia.org)
  • These defects are mediated by increased expression of a protein called Xrp1, which is involved in gene expression regulation. (europa.eu)
  • Xrp1 is a DNA-binding protein that is involved in gene expression regulation. (europa.eu)
  • TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed RNA-binding protein with diverse roles in RNA processing. (lafurnitura.com)
  • Brain expressed X-linked gene 2 (BEX2) encoded protein was originally identified to promote transcription by interacting with several transcription factors in the DNA-binding complexes. (bvsalud.org)
  • TDP-43 is a predominantly nuclear protein, with much known about its nuclear roles in DNA and RNA binding, and regulation of transcription and translation. (edu.au)
  • Several mechanisms for how the non-coding repeat expansion in C9ORF72 may lead to disease have been described, however little is known about the normal function and the expression pattern of the C9ORF72 protein. (edu.au)
  • Analyzing the human transcriptome in this way, we identified more than 12,000 methylated sites in mRNA molecules derived from approximately 7,000 protein-coding genes. (pharmaceuticalintelligence.com)
  • Microtubule-associated protein tau encoded by the MAPT gene binds to microtubules and is important for maintaining neuronal morphology and function. (biomedcentral.com)
  • Enhanced viability of a nervous necrosis virus-infected stable cell line over-expressing a fusion product of the zfBcl-XL and green fluorescent protein genes. (sinica.edu.tw)
Trinucleotide2
20192
  • These modifications influence many cellular processes including transcription, RNA processing, signal transduction cascades, DNA damage response, and liquid-liquid phase separation ( Guccione and Richard, 2019 ). (frontiersin.org)
  • 2019. Convergent evidence that ZNF804A is a regulator of pre-messenger RNA processing and gene expression . (cardiff.ac.uk)
Designed to detect1
  • Some of these tools are designed to detect STR expansions at disease-related loci, while others detect expansions and contractions of STRs genome-wide but are constrained by sequencing read length and the STR motif size. (biomedcentral.com)
Addition to genes1
  • The PGx Comprehensive Panel includes genes associated with drug metabolism with high level evidence and clinically actionable guidelines, in addition to genes with PharmGKB evidence of 2 or higher. (fulgentgenetics.com)
Phenotype5
  • The observation of pleiotropy has emerged, with mutations in the same gene giving rise to diverse phenotypes, which further increases the complexity of phenotype-genotype correlation. (biomedcentral.com)
  • This test cannot rule out the possibility that the tested individual has a rare or uncharacterized phenotype for genes on this panel. (fulgentgenetics.com)
  • The C9orf72 hexanucleotide repeat expansion led to haploinsufficiency resulting in severely defective intracellular and extracellular vesicle trafficking and a dysfunctional trans-Golgi network phenotype in patient-derived fibroblasts and induced pluripotent stem cell-derived motor neurons. (ox.ac.uk)
  • In this review, we will delineate the clinical features of ALS, outline the major ALS-related genes, and summarize the possible genotype-phenotype correlations of ALS. (biomedcentral.com)
  • In what is often described as an 'intermediate phenotype' or 'endophenotype' approach, studying these brain based 'phenotypes' may help bring us closer to the mechanism of gene activity so as to understand the broader illness phenotype. (universityofgalway.ie)
Risk genes2
  • Identification of both causal and risk genes will help build a more complete picture of the underlying mechanisms and pathways for disease and any new ALS molecule is potentially a new therapeutic target [ 8 ]. (biomedcentral.com)
  • To do this our work draws on neuropsychological, electrophysiological, and neuro-imaging techniques for investigating the role of gene function at the level of individual brain systems.This work has led to a number of important insights into newly discovered risk genes for psychosis. (universityofgalway.ie)
1,6002
  • 30 repeats of this hexanucleotide, approximately 8-10% of FTD and ALS European patients carry very large expansions which have been reported to range between 700 and 1,600 repeats 5 . (nature.com)
  • 2011). Affected individuals had expanded repeat units ranging from 700 to 1,600. (coriell.org)
Sequence4
  • Cumulative data shows that Pur-alpha preferentially binds to the sequence (G2-4N1-3)n, where N is not G. N denotes a nucleotide, and n denotes the number of repeats of this small sequence. (wikipedia.org)
  • N may be repeated up to three times in this sequence. (wikipedia.org)
  • scolymus) has been used to catalog the genome's content of simple sequence repeat (SSR) markers. (researchgate.net)
  • The negative supercoiling of DNA can induce sequence-dependent conformational changes that give rise to local DNA structures and alternative DNA conformations such as cruciforms, A-DNA, left-handed DNA (Z-DNA), triplexes, four-stranded DNA (quadruplexes) and others [ 2 , 3 ]( ref )" But we don't really get into most of those other types here. (anti-agingfirewalls.com)
Identifying2
  • Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. (biomedcentral.com)
  • We performed a systematic analysis of blood DNA methylation profiles from 4,483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia and treatment-resistant schizophrenia. (elifesciences.org)
Mutations in the gene1
  • The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. (nih.gov)
Methylation3
  • Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. (elifesciences.org)
  • Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. (elifesciences.org)
  • Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia. (elifesciences.org)
Loci1
  • It is a highly heterogeneous group of disorders, with more than 80 genes or loci implicated [ 3 ]. (biomedcentral.com)
Detect1
  • This assay will not detect certain types of genomic aberrations such as translocations, inversions, or repeat expansions (eg. (fulgentgenetics.com)
Prevalent cause1
  • Hexanucleotide repeat expansions in a gene called C9orf72 are the most prevalent cause of familial ALS. (europa.eu)
Causal1
  • A causal role for TDP-43 assembly in neurodegeneration is evidenced by dominantly inherited missense mutations in TARDBP, the gene encoding TDP-43, that promote assembly and give rise to ALS and FTLD3,4,5,6,7. (lafurnitura.com)
Termed G-quadruplexes1
  • G-rich sequences have a propensity for forming highly stable quadruplex structures in both RNA and DNA termed G-quadruplexes. (nature.com)
Pathogenesis1
  • When C9ORF72 was overexpressed or antisense oligonucleotides were targeted to the C9orf72 hexanucleotide repeat expansion to upregulate normal variant 1 transcript levels, the defective vesicle trafficking and dysfunctional trans-Golgi network phenotypes were reversed, suggesting that both loss- and gain-of-function mechanisms play a role in disease pathogenesis. (ox.ac.uk)
Familial5
  • The five major genes previously identified for ALS account for approximately 25 percent of familial cases. (nih.gov)
  • Further analysis identified this expanded hexanucleotide repeat in 16 (61.5%) of a series of 26 families with the disorder, as well as in 11.7% of familial FTD and 23.5% of familial ALS from 3 patient series. (coriell.org)
  • 2011). The expanded repeat was also found in 46.4% of Finnish familial ALS cases and in 21% of sporadic cases. (coriell.org)
  • In addition, an expanded repeat was found in 102 (38.1%) of 268 familial ALS probands of European origin. (coriell.org)
  • Mutations in the C9orf72 gene are responsible for 30-40% of familial ALS cases in the United States and Europe. (medscape.com)
Imperfect2
  • A total of 4,761 perfect and 6,583 imperfect SSRs were present in 3,781 genes (14.11% of the total), corresponding to an overall density across the gene space of 32,5 and 44,9 SSRs/Mbp for perfect and imperfect motifs, respectively. (researchgate.net)
  • Perfect repeats mutate about 2 × more often than imperfect repeats. (biomedcentral.com)
Genome1
  • No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. (biomedcentral.com)
Oligogenic1
  • Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene, presence of modifier genes, and oligogenic inheritance. (biomedcentral.com)
Humans1
  • In humans Pur-alpha functions to activate transcription in the nucleus, to facilitate RNA transport in the cytoplasm and to regulate DNA replication in the cell cycle. (wikipedia.org)
Motor neurons1
  • In ALS, a progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system, the C9ORF72 gene accounts for 40 percent of inherited forms of the disease and 6 percent of sporadic cases. (lifeboat.com)
Nucleotides1
  • This string of six nucleotides (known as a hexanucleotide) is represented by the letters GGCCTG and normally appears multiple times in a row. (medlineplus.gov)
Motifs1
  • Short tandem repeats (STRs), or microsatellites, are 1-6 base pair (bp) motifs of repeating units of DNA. (biomedcentral.com)
Sporadic1
  • Sporadic cases with the expansion were also identified. (coriell.org)
Sequences1
  • G-quadruplexes are secondary semi-stable folded structures found in our DNA and RNA which tend to assemble around guanine-rich sequences in the presence of cation molecules like potassium. (anti-agingfirewalls.com)
Ontology1
  • A putative function has been assigned, using the gene ontology approach, to the set of genes harboring at least one SSR. (researchgate.net)
Unclear1
  • It is unclear if 15 to 649 repeats of this hexanucleotide cause any signs or symptoms. (medlineplus.gov)
Rs38499421
  • Longer repeats were associated with the A allele at SNP rs3849942, which marked a disease haplotype. (coriell.org)
Pathways1
  • These studies show that both mitochondrial function and DNA repair pathways are disrupted when the mutated gene is present in cells. (lifeboat.com)
Variant1
  • To meta-analyse our results with a published study of European ancestry, we used a Cochran-Mantel-Haenszel test to compare gene-level variant counts in cases vs controls. (biomedcentral.com)
MRNA1
  • However, a large increase in the number of GGCCTG repeats in the NOP56 gene disrupts the normal structure of NOP56 mRNA. (medlineplus.gov)
Mechanism1
  • Here we show using NMR and CD spectroscopy that the C9orf72 hexanucleotide expansion can form a stable G-quadruplex, which has profound implications for disease mechanism in ALS and FTD. (nature.com)
Unusual1
  • These unusual DNA structures play critical roles in regulation of very basic biological functions and are integral part of the complex regulatory systems of living beings. (anti-agingfirewalls.com)
Allele1
  • Those with a risk allele of rs903603 had an excess of apparent homozygosity for wild type repeat alleles, consistent with polymerase chain reaction failure of 1 allele because of massive repeat expansion. (ox.ac.uk)
Researchers1
  • Additionally, researchers believe that the large expansion of the hexanucleotide repeat in the NOP56 gene may reduce the activity of a nearby gene called MIR1292 . (medlineplus.gov)
Promoter2
  • Inflammaging is driven by several factors, such as single nucleotide polymorphisms in the promoter regions of pro- and anti-inflammatory genes, chronic stimulation of immune cells with pathogens, changes in the composition of the gut microbiota, and cellular senescence [ 8 ]. (biomedcentral.com)
  • Heat can affect their coming and going, and their presence near promoter elements can block gene activation. (anti-agingfirewalls.com)
Cellular1
  • And, G-quadruplex formation on single stranded DNA is one of the ways that the telomeric DNA is protected from oxidative stress and from triggering the DNA-damage response (DDR), which causes cellular senescence. (anti-agingfirewalls.com)
Single gene1
  • Customization of this panel and single gene analysis for any gene present on this panel are available. (mayocliniclabs.com)