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Gregory M Williams, Jennifer A Surtees
Trinucleotide repeat (TNR) tracts are inherently unstable during DNA replication, leading to repeat expansions and/or contractions. Expanded tracts are the cause of over 40 neurodegenerative and neuromuscular diseases. In this chapter, we focus on the (CNG)n repeat sequences that, when expanded, lead to Huntington's disease (HD), myotonic dystrophy type 1 (DM1), and a number of other neurodegenerative diseases. We describe a series of in vivo assays, using the model system Saccharomyces cerevisiae, to determine and characterize the dynamic behavior of TNR tracts that are in the early stages of expansion, i...
2018: Methods in Molecular Biology
Elina A Radchenko, Ryan J McGinty, Anna Y Aksenova, Alexander J Neil, Sergei M Mirkin
Instability of repetitive DNA sequences causes numerous hereditary disorders in humans, the majority of which are associated with trinucleotide repeat expansions. Here, we describe a unique system to study instability of triplet repeats in a yeast experimental setting. Using fluctuation assay and the novel program FluCalc we are able to accurately estimate the rates of large-scale expansions, as well as repeat-mediated mutagenesis and gross chromosomal rearrangements for different repeat sequences.
2018: Methods in Molecular Biology
Erica J Polleys, Catherine H Freudenreich
Trinucleotide repeats are common in the human genome and can undergo changes in repeat length. Expanded CAG repeats have been linked to over 14 human diseases and are considered hotspots for breakage and genomic rearrangement. Here, we describe two Saccharomyces cerevisiae based assays that evaluate the rate of chromosome breakage that occurs within a repeat tract (fragility), and a PCR-based assay to evaluate tract length changes (instability). The first fragility assay utilizes end-loss and subsequent telomere addition as the main mode of repair of a yeast artificial chromosome (YAC)...
2018: Methods in Molecular Biology
Caitlin S Latimer, Margaret E Flanagan, Patrick J Cimino, Suman Jayadev, Marie Davis, Zachary S Hoffer, Thomas J Montine, Luis F Gonzalez-Cuyar, Thomas D Bird, C Dirk Keene
BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a trinucleotide (CAG) repeat expansion in huntingtin (HTT) on chromosome 4. Anticipation can cause longer repeat expansions in children of HD patients. Juvenile Huntington's disease (JHD), defined as HD arising before age 20, accounts for 5-10% of HD cases, with cases arising in the first decade accounting for approximately 1%. Clinically, JHD differs from the predominately choreiform adult onset Huntington's disease (AOHD) with variable presentations, including symptoms such as myoclonus, seizures, Parkinsonism, and cognitive decline...
October 11, 2017: Journal of Huntington's Disease
Candice Lesage, Isabelle Coupier, Bernard Guillot
Fragile X syndrome (FXS), a leading cause of inherited intellectual disability, most commonly results from an expansion of the CGG trinucleotide repeat in the fragile X mental retardation 1 (FMR1) gene to more than 200 copies (full mutation). The FXS phenotype differs by sex and is associated with intellectual and cognitive impairment, characteristic physical features, epilepsy, and/or behavioral challenges including autism spectrum disorder. In this patient population, tumors involving blood cells, digestive organs, the central nervous system, and testes have been described, but melanocytic tumors have not been reported...
October 13, 2017: Melanoma Research
Elena Fimmel, Christian J Michel, Lutz Strüngmann
The graph approach of circular codes recently developed (Fimmel et al.,2016) allows here a detailed study of diletter circular codes over finite alphabets. A new class of circular codes is identified, strong comma-free codes. New theorems are proved with the diletter circular codes of maximal length in relation to (i) a characterisation of their graphs as acyclic tournaments; (ii) their explicit description; and (iii) the non-existence of other maximal diletter circular codes. The maximal lengths of paths in the graphs of the comma-free and strong comma-free codes are determined...
October 9, 2017: Mathematical Biosciences
W F A Den Dunnen
Trinucleotide repeat disorders comprise a variable group of inherited neurodegenerative diseases, with a large range in prevalence figures. There is a broad range in clinical presentations, but many of these diseases lead to some form of ataxia or other movement disorders, which are frequently combined with cognitive or psychiatric disturbances. This group can be divided into CAG- versus non-CAG-repeat diseases. Apart from spinocerebellar ataxia type 6 and 12 (SCA6 and SCA12), these CAG-repeat diseases, as well as Huntington disease-like 2 (HDL2) and SCA8, can be neuropathologically identified using 1C2 polyglutamine antibodies...
2017: Handbook of Clinical Neurology
Gabor G Kovacs
Neurodegenerative diseases are disorders characterized by progressive loss of neurons associated with deposition of proteins showing altered physicochemical properties in the brain and in peripheral organs. Molecular classification of neurodegenerative disease is protein-based. This emphasizes the role of protein-processing systems in the pathogenesis. The most frequent proteins involved in the pathogenesis of neurodegenerative diseases are amyloid-β, prion protein, tau, α-synuclein, TAR-DNA-binding protein 43kDa, and fused-in sarcoma protein...
2017: Handbook of Clinical Neurology
Peter A Holmans, Thomas H Massey, Lesley Jones
In the decades since the genes and mutations associated with the commoner Mendelian disorders were first discovered, technological advances in genetic analysis have made finding genomic variation a much less onerous task. Recently, the global efforts to collect subjects with Mendelian disorders, to better define the disorders and to empower appropriate clinical trials, along with improved genetic technologies, have allowed the identification of genetic variation that does not cause disease, but substantially modifies disease presentation...
October 1, 2017: Human Molecular Genetics
Christos Yapijakis
Huntington's chorea or Huntington disease (HD) is a late-onset autosomal dominant neurodegenerative disorder caused by a trinucleotide repeat expansion. The multidisciplinary study of HD has been the focus of an international collaborating effort of basic and applied research for several decades. HD was the first human genetic disease mapped using linkage analysis of DNA polymorphisms and became a paradigm for scores of genes mapped in the same manner. Presymptomatic and prenatal testing have been available for HD families in the last 30 years, following genetic counseling and careful bioethical guidelines...
2017: Advances in Experimental Medicine and Biology
Randi J Hagerman, Elizabeth Berry-Kravis, Heather Cody Hazlett, Donald B Bailey, Herve Moine, R Frank Kooy, Flora Tassone, Ilse Gantois, Nahum Sonenberg, Jean Louis Mandel, Paul J Hagerman
Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which >200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene expression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections...
September 29, 2017: Nature Reviews. Disease Primers
Tanya P Garcia, Karen Marder, Yuanjia Wang
Huntington disease (HD) is caused by a CAG trinucleotide expansion in the huntingtin gene. We now have the power to predict age-at-onset from subject-specific features like motor and neuroimaging measures. In clinical trials, properly modeling onset age is important, because it improves power calculations and directs clinicians to recruit subjects with certain features. The history of modeling onset, from simple linear and logistic regression to advanced survival models, is discussed. We highlight their advantages and disadvantages, emphasizing the methodological challenges when genetic mutation status is unavailable...
2017: Handbook of Clinical Neurology
Chris Kay, Michael R Hayden, Blair R Leavitt
Huntington disease (HD) is an autosomal-dominant neurologic disorder caused by an expanded CAG trinucleotide repeat mutation in patients with characteristic motor signs and specific brain pathology. A repeat of 36 CAG or more can lead to the disease, with increased penetrance and decreased age of onset at longer CAG repeats. The epidemiology of HD thus depends on ascertainment of individuals with the expanded CAG mutation, and on examination of clinical signs to accurately assess disease onset. A larger number of individuals have an expanded CAG repeat than actively manifest the disease due to adult onset in the majority of cases...
2017: Handbook of Clinical Neurology
Carlo Bavassano, Andreas Eigentler, Ruslan Stanika, Gerald J Obermair, Sylvia Boesch, Georg Dechant, Roxana Nat
Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the CACNA1A gene. As one of the few bicistronic genes discovered in the human genome, CACNA1A encodes not only the α1A subunit of the P/Q type voltage-gated Ca2+ channel CaV2.1, but also the α1ACT protein, a 75 kDa transcription factor sharing the sequence of the cytoplasmic C-terminal tail of the α1A subunit. Isoforms of both proteins contain the polyglutamine (polyQ) domain that is expanded in SCA6 patients...
September 25, 2017: Stem Cells and Development
Melanie B Prentice, Jeff Bowman, Jillian L Lalor, Michelle M McKay, Lindsay A Thomson, Cristen M Watt, Andrew G McAdam, Dennis L Murray, Paul J Wilson
Climate change is predicted to affect the reproductive ecology of wildlife; however, we have yet to understand if and how species can adapt to the rapid pace of change. Clock genes are functional genes likely critical for adaptation to shifting seasonal conditions through shifts in timing cues. Many of these genes contain coding trinucleotide repeats, which offer the potential for higher rates of change than single nucleotide polymorphisms (SNPs) at coding sites, and, thus, may translate to faster rates of adaptation in changing environments...
September 2017: Ecology and Evolution
Jae Jun Shin, Young Min Choi, Hwa Young Choi, Soo Jin Chae, Kyuri Hwang, Jin Ju Kim, Gyoung Hoon Lee, Jong Mi Kim
STUDY OBJECTIVE: To investigate the association between the androgen receptor (AR) cytosine, adenine, and guanine (CAG) repeat polymorphisms and endometriosis. STUDY DESIGN: A prospective case-control, genetic association study was performed on women with surgically proven endometriosis (n=421) and controls free of endometriosis (n=349). AR CAG repeat lengths were determined from peripheral blood samples. The difference in the frequency of each alleles were compared in patients with endometriosis and controls using Chi-square test...
September 8, 2017: European Journal of Obstetrics, Gynecology, and Reproductive Biology
Tingting Liang, Bo Zhou, Lei Shi, Han Wang, Qingpo Chu, Feilong Xu, Yuan Li, Ruonan Chen, Chunyan Shen, Allan P Schinckel
Long noncoding RNAs (lncRNAs) have been reported to play diverse roles in biologic and pathologic processes, including myogenesis. We found that lncRNA AK017368 is highly expressed in skeletal muscle cells. Functional analyses showed that overexpression of AK017368 promoted proliferation and restrained differentiation of myoblasts; whereas inhibition of AK017368 had completely opposite effects in vitro In mice, knockdown of AK017368 promoted muscle hypertrophy in vivo RNA molecules of AK017368 acted mechanistically as competing endogenous RNAs to target micro-RNA (miR)-30c, which was supported by the results of bioinformatics analyses and dual-luciferase reporter assays...
September 13, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Juliana A Vianna, Daly Noll, Isidora Mura-Jornet, Paulina Valenzuela-Guerra, Daniel González-Acuña, Cristell Navarro, David E Loyola, Gisele P M Dantas
Microsatellites are valuable molecular markers for evolutionary and ecological studies. Next generation sequencing is responsible for the increasing number of microsatellites for non-model species. Penguins of the Pygoscelis genus are comprised of three species: Adélie (P. adeliae), Chinstrap (P. antarcticus) and Gentoo penguin (P. papua), all distributed around Antarctica and the sub-Antarctic. The species have been affected differently by climate change, and the use of microsatellite markers will be crucial to monitor population dynamics...
July 2017: Genetics and Molecular Biology
E P Lowell, B L Tonnsen, D B Bailey, J E Roberts
BACKGROUND: The FMR1 premutation, caused by a CGG trinucleotide repeat expansion on the FMR1 gene, has been identified as a genetic risk factor for mood and anxiety disorders. Building on recent studies identifying increased risk for mood and affective disorders in this population, we examined effects of potential protective factors (optimism, religion, hope) on depression and anxiety diagnoses in a prospective, longitudinal cohort. METHODS: Eighty-three women with the FMR1 premutation participated in the Structured Clinical Interview for DSM-IV-TR Disorders at two-time points, 3 years apart...
October 2017: Journal of Intellectual Disability Research: JIDR
Bharathikumar Vellalore Maruthachalam, Ayman El-Sayad, Jianghai Liu, Wayne Hill, Ashley Sutherland, Landon Pastushok, Humphrey Fonge, Kris Barreto, Clarence Ronald Geyer
Synthetic antibody libraries have been used to generate antibodies with favorable biophysical and pharmacological properties. Here, we describe the design, construction, and validation of a phage-displayed Fab library built on a modified trastuzumab framework with four fixed and two diversified complementarity-determining regions (CDRs). CDRs L1, L2, H1, and H2 were fixed to preserve the most-frequent 'canonical' CDR conformation preferred by the modified trastuzumab Fab framework. The library diversity was engineered within CDRs L3 and H3 using custom-designed trinucleotide phosphoramidite mixes and biased towards human antibody CDR sequences...
September 7, 2017: Chembiochem: a European Journal of Chemical Biology
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