• mutations
  • A large body of literature has appeared on human disease-associated mutations, normal sequence variation, and alterations that acquire pathological significance when combined with other deleterious alleles or second-site mutations. (biomedcentral.com)
  • In contrast, in mutant strains carrying mutations in proteins involved in DNA replication or repair, expansions are frequently seen. (embopress.org)
  • Mutations in the tau gene cause familial frontotemporal dementia. (genetics.org)
  • Her work focuses on studying heritable traits in humans, linking them back to DNA mutations, and using animal models to further explore the mechanisms underlying various phenotypes and the heritability of these phenotypes. (wikipedia.org)
  • As the underlying pathogenic events in these disorders are dominant gene mutations, simply reducing mutant allele expression may be therapeutic. (fitness-vip.com)
  • Loss-of-function contributions to dominant disease can be predicted from knockout mouse models and by examining genetic case studies, in which different mutations in the same gene give rise to dominant and recessive myopathies. (fitness-vip.com)
  • Recent studies have also found homozygous and compound heterozygous mutations in the TBP gene of SCA17 affected individuals. (cags.org.ae)
  • First, individuals with autism have significantly reduced fecundity, they are 20 times less likely to have children than average, thus curtailing the persistence of mutations in ASD genes over multiple generations in a family. (wikipedia.org)
  • The first genes to be definitively shown to contribute to risk for autism were found in the early 1990s by researchers looking at gender-specific forms of autism caused by mutations on the X chromosome. (wikipedia.org)
  • At this time, there are at least 29 different gene mutations that have been found. (wikipedia.org)
  • Many neurodegenerative diseases are caused by genetic mutations, most of which are located in completely unrelated genes. (wikipedia.org)
  • mutation
  • Replication slippage, otherwise known as slipped-strand mispairing, is a form of mutation that leads to either a trinucleotide or dinucleotide expansion or contraction during DNA replication. (wikipedia.org)
  • Synonymous nucleotide substitutions occur at a higher rate in disease genes, a finding that may reflect increased mutation rates in the chromosomal regions in which disease genes are found. (biomedcentral.com)
  • In another instance, reprogramming a mosaic patient having both normal and pre-mutation length CGG repeats resulted in genetically matched iPSC clonal lines differing in FMR1 promoter CpG methylation and FMRP expression. (nih.gov)
  • They cloned the causative gene/mutation and studied the in vitro biochemical consequences of the mutation, culminating in a 2001 paper An hPer2 phosphorylation site mutation in familial advanced sleep-phase syndrome, reporting the first circadian gene mutation in humans. (wikipedia.org)
  • The lab studied the genomes of people with this trait and found a point mutation in the PER2 gene that likely causes the behavioral phenotype. (wikipedia.org)
  • Fu traced the phenotype back to a point mutation in a gene called DEC2 that is associated with short sleep phenotype in humans. (wikipedia.org)
  • CAG repeats that exceed thirty-five can cause a gain-of-function mutation in ATN1. (wikipedia.org)
  • Whole exome sequencing helped identify a homozygous mutation (c.171delG, p.Q57 fs) in exon 2 of the patient's TBP gene. (cags.org.ae)
  • As TBP is associated with the autosomal dominant SCA17, this finding presented a unique case of a recessive mutation in a gene normally associated with a dominant phenotype. (cags.org.ae)
  • An expansion of the CGG trinucleotide repeat in the promoter of the gene FMR1 in boys causes fragile X syndrome, and at least 20% of boys with this mutation have behaviors consistent with autism spectrum disorder. (wikipedia.org)
  • The disease is caused by an autosomal dominant mutation in either of an individual's two copies of a gene called Huntingtin. (wikipedia.org)
  • However, meiotic instability could result in a dynamic mutation that increases the number of repeats in offspring inheriting the mutant allele. (wikipedia.org)
  • locus
  • Despite the known relationship between FMR1 CGG repeat expansion and FMR1 silencing, the epigenetic modifications observed at the FMR1 locus, and the consequences of the loss of FMRP on human neurodevelopment and neuronal function remain poorly understood. (nih.gov)
  • Overexpression of Mre11p or Rad50p suppresses the inhibition of DSB repair by CAG 98 and significantly increases the average size of expansions found at the recipient locus. (embopress.org)
  • It remains possible that other disease phenotypes are caused by expansions of any repeat motif at any repeat containing locus. (springer.com)
  • citation needed] The hereditary ataxias are categorized by mode of inheritance and causative gene or chromosomal locus. (wikipedia.org)
  • intron
  • The reduction in frataxin gene expression may be attributable from either the silencing of transcription of the frataxin gene because of epigenetic modifications in the chromosomal entity or from the inability of splicing the expanded GAA repeats in the first intron of the pre-mRNA as seen in Bacteria and Human cells or both. (wikipedia.org)
  • proteins
  • Nucleotide excision repair proteins are mobilized to this area where one likely outcome is the expansion of nucleotides in the template strand while the other is the absence of nucleotides. (wikipedia.org)
  • As normal copies of disease genes likely encode essential proteins, normal allele haploinsuffi-ciency may contribute to myopathic phenotypes as well. (fitness-vip.com)
  • causative gene
  • Although expression of the causative gene in each of these diseases is ubiquitous, selective neuronal cell death is observed in disease-specific areas of the CNS, suggesting a common molecular basis for these polyglutamine diseases. (jneurosci.org)
  • sequences
  • Iyer, R. R. and Wells, R. D. (1999) Expansion and deletion of triplet repeat sequences in Escherichia coli occur on the leading strand of DNA. (springer.com)
  • The most prevalent repeated sequences in the embedded microsatellite regions were CCT:AGG, CTT:AAG, CTTT:AAAG, and CCCT:AGGG. (wikipedia.org)
  • These strand biased pyrimidine:purine repeating sequences were shown to adopt triple-stranded structures under superhelical stress or at slightly acidic pH. (wikipedia.org)
  • Variations among cloned RU sequences were characterized by the number of microsatellite repeats, and also by the lengths of C and G stretches where triple stranded structures formed. (wikipedia.org)
  • neuronal
  • Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of the FMR1 gene and a loss of FMRP expression. (nih.gov)
  • We study how synaptic transmission and depolarization cause changes in neuronal gene expression. (stanford.edu)
  • One example of such signaling involves a local increase in Ca2+ concentration near a class of Ca2+ channels (L-type) different from those that trigger presynaptic transmitter release, subsequently leading to activation of an exemplar transcription factor, CREB, a regulator of transcription of many important neuronal genes. (stanford.edu)
  • How polyglutamine expansion in Ataxin-1 causes neuronal dysfunction and degeneration is still unclear. (wikipedia.org)
  • diseases
  • Replication slippage can also lead to other neurodegenerative diseases in humans. (wikipedia.org)
  • In support of this hypothesis, altered expression of a variety of genes has been demonstrated in transgenic mouse models of polyglutamine diseases ( Sugars and Rubinsztein, 2003 ). (jneurosci.org)
  • Although polyglutamine-induced transcriptional dysregulation is likely to be central to the pathogenesis of polyglutamine diseases, it has yet to be elucidated which genes are responsible for the selective neurodegeneration ( Gatchel and Zoghbi, 2005 ). (jneurosci.org)
  • There is a widely held expectation that genomic studies will lead to advances in the diagnosis and treatment of diseases, and to new insights in many fields of biology, including human evolution . (wikipedia.org)
  • An inverse correlation between the repeat length and disease severity/earlier age of onset, known as anticipation, has been observed in most of the families transmitting such types of diseases, suggesting that the length change of the repeats may play a role in the manifestation of anticipation. (springer.com)
  • In many of the different diseases, the mutated gene has a common feature: a repeat of the CAG nucleotide triplet. (wikipedia.org)
  • For a complete list, see the table under Polyglutamine (PolyQ) Diseases in the article Trinucleotide repeat disorder. (wikipedia.org)
  • FRATAXIN
  • This expanded repeat causes R-loop formation, and using a repeat-targeted oligonucleotide to disrupt the R-loop can reactivate frataxin expression. (wikipedia.org)
  • epigenetic
  • Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. (nih.gov)
  • allele
  • The disease allele usually contains 34-52 CAG repeats, but can contain as few as 32 or more than 100, and can expand in size when transmitted to successive generations. (wikipedia.org)
  • Likewise, disease allele-specific RNAi therapies may be important for Caveolin-3-related myopathies, as normal Cav-3 gene dosage impacts muscle disease severity (Carbone et al. (fitness-vip.com)
  • 2008). In both NM and LGMD1C examples, it would be advantageous to restrict gene knockdown to the affected allele while leaving the normal allele unperturbed. (fitness-vip.com)
  • citation needed] There have been reported cases where a polyglutamine expansion may lengthen when passed down, which often can result in an earlier age-of-onset and a more severe disease phenotype for individuals who inherit the disease allele. (wikipedia.org)
  • Genomes
  • The HD gene is found in all human genomes. (wikipedia.org)
  • Most human disease genes have been retained in rodent genomes. (biomedcentral.com)
  • Haploid human genomes, which are contained in germ cells (the egg and sperm gamete cells created in the meiosis phase of sexual reproduction before fertilization creates a zygote ) consist of three billion DNA base pairs , while diploid genomes (found in somatic cells ) have twice the DNA content. (wikipedia.org)
  • While there are significant differences among the genomes of human individuals (on the order of 0.1%), these are considerably smaller than the differences between humans and their closest living relatives, the chimpanzees (approximately 4% ) and bonobos . (wikipedia.org)
  • As of 2012, thousands of human genomes have been completely sequenced, and many more have been mapped at lower levels of resolution. (wikipedia.org)
  • microsatellites
  • This class of microsatellites has the property of undergoing rapid and sometimes massive expansion of their repeat number, during germline transmission or early embryogenesis. (embopress.org)
  • One striking feature of all expansion‐associated microsatellites is their propensity to form secondary structures. (embopress.org)
  • FMR1
  • We show that clones from reprogrammed FXS patient fibroblast lines exhibit variation with respect to the predominant CGG-repeat length in the FMR1 gene. (nih.gov)
  • A) Predominant CGG-repeat size in the FMR1 promoter as determined by Southern blot analysis. (nih.gov)
  • Knock-out of the Fmr1 gene in mice removes FMRP and mimics FXS in humans ( O'Donnell and Warren, 2002 ). (jneurosci.org)
  • 2001
  • In 2001, Fu and her collaborator's labs published a paper that explained a phenotype of extremely early risers in humans called Familial Advanced Sleep Phase Syndrome (FASPS). (wikipedia.org)
  • polymerase
  • Slippage occurs through five main stages: In the first step, DNA polymerase encounters the direct repeat during the replication process. (wikipedia.org)
  • DNA polymerase reassembles its position on the template strand and resumes normal replication, but during the course of reassembling, the polymerase complex backtracks and repeats the insertion of deoxyribonucleotides that were previously added. (wikipedia.org)
  • One hypothesis is that the increasing number of repeats influence the overall shape of the DNA, which can have an effect on its interaction with DNA polymerase and thus the expression of the gene. (wikipedia.org)
  • promoter
  • It appears to be involved in regulating gene expression based on its location in the nucleus of the cell, its association with promoter regions of several genes, and its interactions with transcriptional regulators and parts of the RNA splicing machinery. (wikipedia.org)