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Fragile X Syndrome

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https://www.readbyqxmd.com/read/29223504/potential-pathogenic-mechanisms-underlying-fragile-x-tremor-ataxia-syndrome-ran-translation-and-or-rna-gain-of-function
#1
REVIEW
Manon Boivin, Rob Willemsen, Renate K Hukema, Chantal Sellier
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disease caused by an expansion of 55-200 CGG repeats located in the FMR1 gene. The main clinical and neuropathological features of FXTAS are progressive intention tremor and gait ataxia associated with brain atrophy, neuronal cell loss and presence of ubiquitin-positive intranuclear inclusions in both neurons and astrocytes. At the molecular level, FXTAS is characterized by increased expression of FMR1 sense and antisense RNA containing expanded CGG or GGC repeats, respectively...
December 6, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29222490/ran-translation-at-c9orf72-associated-repeat-expansions-is-selectively-enhanced-by-the-integrated-stress-response
#2
Katelyn M Green, M Rebecca Glineburg, Michael G Kearse, Brittany N Flores, Alexander E Linsalata, Stephen J Fedak, Aaron C Goldstrohm, Sami J Barmada, Peter K Todd
Repeat-associated non-AUG (RAN) translation allows for unconventional initiation at disease-causing repeat expansions. As RAN translation contributes to pathogenesis in multiple neurodegenerative disorders, determining its mechanistic underpinnings may inform therapeutic development. Here we analyze RAN translation at G4C2 repeat expansions that cause C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9RAN) and at CGG repeats that cause fragile X-associated tremor/ataxia syndrome...
December 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/29221753/pura-the-gene-encoding-pur-alpha-member-of-an-ancient-nucleic-acid-binding-protein-family-with-mammalian-neurological-functions
#3
REVIEW
Dianne C Daniel, Edward M Johnson
The PURA gene encodes Pur-alpha, a 322 amino acid protein with repeated nucleic acid binding domains that are highly conserved from bacteria through humans. PUR genes with a single copy of this domain have been detected so far in spirochetes and bacteroides. Lower eukaryotes possess one copy of the PUR gene, whereas chordates possess 1-4 PUR family members. Human PUR genes encode Pur-alpha (Pura), Pur-beta (Purb) and two forms of Pur-gamma (Purg). Pur-alpha is a protein that binds specific DNA and RNA sequence elements...
December 5, 2017: Gene
https://www.readbyqxmd.com/read/29218006/reduced-levels-of-the-synaptic-functional-regulator-fmrp-in-dentate-gyrus-of-the-aging-sprague-dawley-rat
#4
Roman Smidak, Fernando J Sialana, Martina Kristofova, Tamara Stojanovic, Dragana Rajcic, Jovana Malikovic, Daniel D Feyissa, Volker Korz, Harald Hoeger, Judit Wackerlig, Diana Mechtcheriakova, Gert Lubec
Fragile X mental retardation protein (FMRP) encoded by Fragile X mental retardation 1 (FMR1) gene is a RNA-binding regulator of mRNA translation, transport and stability with multiple targets responsible for proper synaptic function. Epigenetic silencing of FMR1 gene expression leads to the development of Fragile X syndrome (FXS) that is characterized by intellectual disability and other behavioral problems including autism. In the rat FXS model, the lack of FMRP caused a deficit in hippocampal-dependent memory...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29217836/drug-development-for-neurodevelopmental-disorders-lessons-learned-from-fragile-x-syndrome
#5
REVIEW
Elizabeth M Berry-Kravis, Lothar Lindemann, Aia E Jønch, George Apostol, Mark F Bear, Randall L Carpenter, Jacqueline N Crawley, Aurore Curie, Vincent Des Portes, Farah Hossain, Fabrizio Gasparini, Baltazar Gomez-Mancilla, David Hessl, Eva Loth, Sebastian H Scharf, Paul P Wang, Florian Von Raison, Randi Hagerman, Will Spooren, Sébastien Jacquemont
Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches...
December 8, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29217098/prolonged-time-lag-to-final-diagnosis-of-fragile-x-syndrome
#6
Lidia V Gabis, Oded Hochberg, Odelia Leon Attia, Yonit Banet-Levi, Dana Topf, Shahar Shefer
OBJECTIVE: To evaluate the diagnostic process in children ultimately diagnosed with fragile X syndrome (FXS), with an emphasis on the time lag between initial presentation and on diagnosis in female vs male children. STUDY DESIGN: Interviews were conducted with 89 families of children with a final diagnosis of FXS and assessment of time intervals between initial presentation and confirmed molecular diagnosis. RESULTS: Screening of 117 patients (25 female patients) from the 89 families revealed that less than 20% of patients obtained a diagnosis within the first year of seeking medical attention...
December 5, 2017: Journal of Pediatrics
https://www.readbyqxmd.com/read/29212015/opposing-post-transcriptional-control-of-inr-by-fmrp-and-lin-28-adjusts-stem-cell-based-tissue-growth
#7
Arthur Luhur, Kasun Buddika, Ishara Surangi Ariyapala, Shengyao Chen, Nicholas Samuel Sokol
Although the intrinsic mechanisms that control whether stem cells divide symmetrically or asymmetrically underlie tissue growth and homeostasis, they remain poorly defined. We report that the RNA-binding protein fragile X mental retardation protein (FMRP) limits the symmetric division, and resulting expansion, of the stem cell population during adaptive intestinal growth in Drosophila. The elevated insulin sensitivity that FMRP-deficient progenitor cells display contributes to their accelerated expansion, which is suppressed by the depletion of insulin-signaling components...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29211876/interplay-between-fmrp-and-lncrna-tug1-regulates-axonal-development-through-mediating-snon-ccd1-pathway
#8
Ye Guo, Xu Chen, Ruxiao Xing, Min Wang, Xiaojuan Zhu, Weixiang Guo
LncRNAs have recently emerged to influence the pathogenesis of fragile X syndrome (FXS), which is caused by the functional loss of fragile X mental retardation protein (FMRP). However, the interaction between FMRP and lncRNAs on regulating neuronal development remains elusive. Here, we reported that FMRP directly interacted with lncRNA TUG1, and decreased its stability. Furthermore, TUG1 bond to transcriptional regulator, SnoN, and negatively modulated SnoN-Ccd1 pathway to specifically control axonal development...
December 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29209628/inhibitors-of-histone-deacetylases-are-weak-activators-of-the-fmr1-gene-in-fragile-x-syndrome-cell-lines
#9
Alexander A Dolskiy, Vladimir O Pustylnyak, Andrey A Yarushkin, Natalya A Lemskaya, Dmitry V Yudkin
Fragile X syndrome is the most common cause of inherited intellectual disability in humans. It is a result of CGG repeat expansion in the 5' untranslated region (5' UTR) of the FMR1 gene. This gene encodes the FMRP protein that is involved in neuronal development. Repeat expansion leads to heterochromatinization of the promoter, gene silencing, and the subsequent absence of FMRP. To date, there is no specific therapy for the syndrome. All treatments in clinic practice provide symptomatic therapy. The development of drug therapy for Fragile X syndrome treatment is connected with the search for inhibitors of enzymes that are responsible for heterochromatinization...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29188551/molecular-characterization-of-fmr1-gene-by-tp-pcr-in-women-of-reproductive-age-and-women-with-premature-ovarian-insufficiency
#10
Deepika Delsa Dean, Sarita Agarwal, Deepa Kapoor, Kuldeep Singh, Chandra Vati
BACKGROUND: Fragile X syndrome is caused by CGG repeat expansion mutation in the FMR1 gene. Normal alleles have 5-44 CGG repeats with AGG interruptions. The expanded gray zone (GZ) (45-54 repeats) and premutation (PM) (55-200 repeats) alleles are often uninterrupted and are unstably inherited in subsequent generations. The prevalence of PM and GZ carriers is high in the female population, at 1/66 and 1/113, respectively, and PM is associated with fertility problems in 20% of cases. OBJECTIVE: Our objective was to molecularly characterize CGG repeats and AGG interruption sequences in the FMR1 gene in women of reproductive age and in women with premature ovarian insufficiency (POI)...
November 29, 2017: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/29178241/rare-fmr1-gene-mutations-causing-fragile-x-syndrome-a-review
#11
Adam F Sitzmann, Robert T Hagelstrom, Flora Tassone, Randi J Hagerman, Merlin G Butler
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, typically due to CGG-repeat expansions in the FMR1 gene leading to lack of expression. We identified a rare FMR1 gene mutation (c.413G>A), previously reported in a single patient and reviewed the literature for other rare FMR1 mutations. Our patient at 10 years of age presented with the classical findings of FXS including intellectual disability, autism, craniofacial findings, hyperextensibility, fleshy hands, flat feet, unsteady gait, and seizures but without the typical CGG-repeat expansion...
November 27, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29171019/cortisol-profiles-differentiated-in-adolescents-and-young-adult-males-with-fragile-x-syndrome-versus-autism-spectrum-disorder
#12
Sara M Matherly, Jessica Klusek, Angela J Thurman, Andrea McDuffie, Leonard Abbeduto, Jane E Roberts
BACKGROUND: Fragile X syndrome (FXS) and non-syndromic autism spectrum disorder (ASD) are distinct disorders with overlapping behavioral features. Both disorders are also highly associated with anxiety with abnormal physiological regulation implied mechanistically. Some reports suggest atypical hypothalamus-pituitary-adrenal (HPA) axis function, indexed via aberrant cortisol reactivity, in both FXS and non-syndromic ASD. However, no study has compared cortisol reactivity across these two disorders, or its relationship to ASD symptom severity...
November 24, 2017: Developmental Psychobiology
https://www.readbyqxmd.com/read/29170682/adaptive-skill-trajectories-in-infants-with-fragile-x-syndrome-contrasted-to-typical-controls-and-infants-at-high-risk-for-autism
#13
Kelly E Caravella, Jane E Roberts
Background: Adaptive behaviors are essential for optimal outcomes and independence in individuals with developmental disabilities. This study examined longitudinal trajectories of adaptive behavior in infants with fragile X syndrome (FXS), compared to typical development (TD) and infant siblings of children diagnosed with autism (ASIBs). Method: Participants included 76 male infants (FXS =25, ASIBs=27, TD = 24) assessed up to 4 times between 6 and 24 months of age for a total of 215 assessments of adaptive behavior...
August 2017: Research in Autism Spectrum Disorders
https://www.readbyqxmd.com/read/29170104/unraveling-unusual-x-chromosome-patterns-during-fragile-x-syndrome-genetic-testing
#14
Gabriella Esposito, Maria Roberta Tremolaterra, Maria Savarese, Michele Spiniello, Maria Pia Patrizio, Barbara Lombardo, Lucio Pastore, Francesco Salvatore, Antonella Carsana
BACKGROUND: Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID). Together with fragile X-associated tremor and ataxia (FXTAS) and fragile X-associated premature ovarian failure (POF)/primary ovarian insufficiency (POI), depends on dysfunctional expression of the FMR1 gene on Xq27.3. In most cases, FXS is caused by a >200 CGG repeats in FMR1 5'-untranslated region (UTR) and by promoter hypermethylation that results in gene silencing. Males and females with unmethylated premutated alleles (repeats between 55 and 200) are at risk for FXTAS and POF/POI...
November 20, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29163124/the-search-for-an-effective-therapy-to-treat-fragile-x-syndrome-dream-or-reality
#15
REVIEW
Sara Castagnola, Barbara Bardoni, Thomas Maurin
Fragile X Syndrome (FXS) is the most common form of intellectual disability and a primary cause of autism. It originates from the lack of the Fragile X Mental Retardation Protein (FMRP), which is an RNA-binding protein encoded by the Fragile X Mental Retardation Gene 1 (FMR1) gene. Multiple roles have been attributed to this protein, ranging from RNA transport (from the nucleus to the cytoplasm, but also along neurites) to translational control of mRNAs. Over the last 20 years many studies have found a large number of FMRP mRNA targets, but it is still not clear which are those playing a critical role in the etiology of FXS...
2017: Frontiers in Synaptic Neuroscience
https://www.readbyqxmd.com/read/29163043/combination-therapy-in-fragile-x-syndrome-possibilities-and-pitfalls-illustrated-by-targeting-the-mglur5-and-gaba-pathway-simultaneously
#16
Shimriet Zeidler, Helen de Boer, Renate K Hukema, Rob Willemsen
Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability and autism. The disorder is characterized by altered synaptic plasticity in the brain. Synaptic plasticity is tightly regulated by a complex balance of different synaptic pathways. In FXS, various synaptic pathways are disrupted, including the excitatory metabotropic glutamate receptor 5 (mGluR5) and the inhibitory γ-aminobutyric acid (GABA) pathways. Targeting each of these pathways individually, has demonstrated beneficial effects in animal models, but not in patients with FXS...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29162813/chemogenomic-analysis-reveals-key-role-for-lysine-acetylation-in-regulating-arc-stability
#17
Jasmin Lalonde, Surya A Reis, Sudhir Sivakumaran, Carl S Holland, Hendrik Wesseling, John F Sauld, Begum Alural, Wen-Ning Zhao, Judith A Steen, Stephen J Haggarty
The role of Arc in synaptic plasticity and memory consolidation has been investigated for many years with recent evidence that defects in the expression or activity of this immediate-early gene may also contribute to the pathophysiology of brain disorders including schizophrenia and fragile X syndrome. These results bring forward the concept that reversing Arc abnormalities could provide an avenue to improve cognitive or neurological impairments in different disease contexts, but how to achieve this therapeutic objective has remained elusive...
November 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/29161443/fragile-x-syndrome-with-congenital-diaphragmatic-hernia
#18
Archana Kadam, Anand Pandit, Sanjay Patole
The authors present a case of Fragile X syndrome (FXS) in siblings from an Indian family with no developmental delay in previous generations. The boy presented with developmental delay, autistic features and defiant behaviours that raised clinical suspicion. He also had congenital diaphragmatic hernia (CDH). Social anxiety and difficulty in making friends were the subtle features in his sister with dull normal intelligence. FXS was confirmed by clinical features and DNA testing. Intervention was initiated for both the siblings...
November 17, 2017: Journal of Tropical Pediatrics
https://www.readbyqxmd.com/read/29151796/association-of-fragile-x-syndrome-robertsonian-translocation-13-22-and-autism-in-a-child
#19
Andreea Liana Rachisan, Alexandru Stefan Niculae, Ioana Tintea, Bianca Pop, Mariela Militaru, Aurel Bizo, Adrian Hrusca
We describe the case of a 6-year-old boy with both fragile X syndrome and Robertsonian Translocation (45, XY, der (13; 22) (q10; q10)). This is the first reported case of a patient with fragile X syndrome with this Robertsonian translocation. Facial features and macroorchidism were consistent with fragile X syndrome. Cognitive impairment is more significant than in his sibling with fragile X syndrome, and the patient also has a prior diagnosis of autism spectrum disorder. We emphasize the challenges in his behavioral management and outline future directions for his management...
2017: Clujul Medical (1957)
https://www.readbyqxmd.com/read/29144507/the-fragile-x-mental-retardation-protein-regulates-tumor-invasiveness-related-pathways-in-melanoma-cells
#20
Francesca Zalfa, Vincenzo Panasiti, Simone Carotti, Maria Zingariello, Giuseppe Perrone, Laura Sancillo, Laura Pacini, Flavie Luciani, Vincenzo Roberti, Silvia D'Amico, Rosa Coppola, Simona Osella Abate, Rosa Alba Rana, Anastasia De Luca, Mark Fiers, Valentina Melocchi, Fabrizio Bianchi, Maria Giulia Farace, Tilmann Achsel, Jean-Christophe Marine, Sergio Morini, Claudia Bagni
The fragile X mental retardation protein (FMRP) is lacking or mutated in patients with the fragile X syndrome (FXS), the most frequent form of inherited intellectual disability. FMRP affects metastasis formation in a mouse model for breast cancer. Here we show that FMRP is overexpressed in human melanoma with high Breslow thickness and high Clark level. Furthermore, meta-analysis of the TCGA melanoma data revealed that high levels of FMRP expression correlate significantly with metastatic tumor tissues, risk of relapsing and disease-free survival...
November 16, 2017: Cell Death & Disease
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