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https://www.readbyqxmd.com/read/28525759/modeling-rett-syndrome-using-talen-edited-mecp2-mutant-cynomolgus-monkeys
#1
Yongchang Chen, Juehua Yu, Yuyu Niu, Dongdong Qin, Hailiang Liu, Gang Li, Yingzhou Hu, Jiaojian Wang, Yi Lu, Yu Kang, Yong Jiang, Kunhua Wu, Siguang Li, Jingkuan Wei, Jing He, Junbang Wang, Xiaojing Liu, Yuping Luo, Chenyang Si, Raoxian Bai, Kunshan Zhang, Jie Liu, Shaoyong Huang, Zhenzhen Chen, Shuang Wang, Xiaoying Chen, Xinhua Bao, Qingping Zhang, Fuxing Li, Rui Geng, Aibin Liang, Dinggang Shen, Tianzi Jiang, Xintian Hu, Yuanye Ma, Weizhi Ji, Yi Eve Sun
Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT...
May 18, 2017: Cell
https://www.readbyqxmd.com/read/28524723/l1-retrotransposition-is-activated-by-ten-eleven-translocation-protein-1-and-repressed-by-methyl-cpg-binding-proteins
#2
Peng Zhang, Anne K Ludwig, Florian D Hastert, Cathia Rausch, Anne Lehmkuhl, Ines Hellmann, Martha Smets, Heinrich Leonhardt, M Cristina Cardoso
One of the major functions of DNA methylation is the repression of transposable elements, such as the long-interspersed nuclear element 1 (L1). The underlying mechanism(s), however, are unclear. Here, we addressed how retrotransposon activation and mobilization are regulated by methyl-cytosine modifying ten-eleven-translocation (Tet) proteins and how this is modulated by methyl-CpG binding domain (MBD) proteins. We show that Tet1 activates both, endogenous and engineered L1 retrotransposons. Furthermore, we found that Mecp2 and Mbd2 repress Tet1-mediated activation of L1 by preventing 5hmC formation at the L1 promoter...
May 19, 2017: Nucleus
https://www.readbyqxmd.com/read/28523560/stem-cell-technology-for-epi-genetic-brain-disorders
#3
Renzo J M Riemens, Edilene S Soares, Manel Esteller, Raul Delgado-Morales
Despite the enormous efforts of the scientific community over the years, effective therapeutics for many (epi)genetic brain disorders remain unidentified. The common and persistent failures to translate preclinical findings into clinical success are partially attributed to the limited efficiency of current disease models. Although animal and cellular models have substantially improved our knowledge of the pathological processes involved in these disorders, human brain research has generally been hampered by a lack of satisfactory humanized model systems...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28523558/epigenome-editing-in-the-brain
#4
Pavel Bashtrykov, Albert Jeltsch
Epigenome editing aims for an introduction or removal of chromatin marks at a defined genomic region using artificial EpiEffectors resulting in a modulation of the activity of the targeted functional DNA elements. Rationally designed EpiEffectors consist of a targeting DNA-binding module (such as a zinc finger protein, TAL effector, or CRISPR/Cas complex) and usually, but not exclusively, a catalytic domain of a chromatin-modifying enzyme. Epigenome editing opens a completely new strategy for basic research of the central nervous system and causal treatment of psychiatric and neurological diseases, because rewriting of epigenetic information can lead to the direct and durable control of the expression of disease-associated genes...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28523539/the-role-of-noncoding-rnas-in-neurodevelopmental-disorders-the-case-of-rett-syndrome
#5
Aida Obiols-Guardia, Sònia Guil
Current technologies have demonstrated that only a small fraction of our genes encode for protein products. The vast majority of the human transcriptome corresponds to noncoding RNA (ncRNA) of different size, localization, and expression profile. Despite the fact that a biological function remains yet to be determined for most ncRNAs, growing evidence points to their crucial regulatory roles at all stages in gene expression regulation, including transcriptional and posttranscriptional control, so that proper cell homeostasis seems to depend largely on a variety of ncRNA-mediated regulatory networks...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28523538/mecp2-a-modulator-of-neuronal-chromatin-organization-involved-in-rett-syndrome
#6
Alexia Martínez de Paz, Juan Ausió
From an epigenetic perspective, the genomic chromatin organization of neurons exhibits unique features when compared to somatic cells. Methyl CpG binding protein 2 (MeCP2), through its ability to bind to methylated DNA, seems to be a major player in regulating such unusual organization. An important contribution to this uniqueness stems from the intrinsically disordered nature of this highly abundant chromosomal protein in neurons. Upon its binding to methylated/hydroxymethylated DNA, MeCP2 is able to recruit a plethora of interacting protein and RNA partners...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28522374/population-pharmacokinetics-of-nnz-2566-in-healthy-subjects
#7
Sean P Oosterholt, Joseph Horrigan, Nancy Jones, Larry Glass, Oscar Della Pasqua
NNZ-2566 is a novel, small molecule being developed as a treatment for cognitive impairment in different CNS conditions, including Rett and Fragile-X syndrome, both of which are associated with moderate to severe neurodevelopmental disorder. In current study we characterise the population pharmacokinetics of NNZ-2566 after administration of single and repeated ascending doses to healthy subjects. A meta-analytical approach was used to analyse pharmacokinetic data from 3 different studies, in which a total of 61 healthy subjects (median age 23years, range 19 to 38) were treated with NNZ-2566...
May 15, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28498846/mecp2-recognizes-cytosine-methylated-tri-nucleotide-and-di-nucleotide-sequences-to-tune-transcription-in-the-mammalian-brain
#8
Sabine Lagger, John C Connelly, Gabriele Schweikert, Shaun Webb, Jim Selfridge, Bernard H Ramsahoye, Miao Yu, Chuan He, Guido Sanguinetti, Lawrence C Sowers, Malcolm D Walkinshaw, Adrian Bird
Mutations in the gene encoding the methyl-CG binding protein MeCP2 cause several neurological disorders including Rett syndrome. The di-nucleotide methyl-CG (mCG) is the classical MeCP2 DNA recognition sequence, but additional methylated sequence targets have been reported. Here we show by in vitro and in vivo analyses that MeCP2 binding to non-CG methylated sites in brain is largely confined to the tri-nucleotide sequence mCAC. MeCP2 binding to chromosomal DNA in mouse brain is proportional to mCAC + mCG density and unexpectedly defines large genomic domains within which transcription is sensitive to MeCP2 occupancy...
May 12, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28497075/development-of-a-novel-aav-gene-therapy-cassette-with-improved-safety-features-and-efficacy-in-a-mouse-model-of-rett-syndrome
#9
Kamal K E Gadalla, Thishnapha Vudhironarit, Ralph D Hector, Sarah Sinnett, Noha G Bahey, Mark E S Bailey, Steven J Gray, Stuart R Cobb
Rett syndrome (RTT), caused by loss-of-function mutations in the MECP2 gene, is a neurological disorder characterized by severe impairment of motor and cognitive functions. The aim of this study was to investigate the impact of vector design, dosage, and delivery route on the efficacy and safety of gene augmentation therapy in mouse models of RTT. Our results show that AAV-mediated delivery of MECP2 to Mecp2 null mice by systemic administration, and utilizing a minimal endogenous promoter, was associated with a narrow therapeutic window and resulted in liver toxicity at higher doses...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28497072/improved-mecp2-gene-therapy-extends-the-survival-of-mecp2-null-mice-without-apparent-toxicity-after-intracisternal-delivery
#10
Sarah E Sinnett, Ralph D Hector, Kamal K E Gadalla, Clifford Heindel, Daphne Chen, Violeta Zaric, Mark E S Bailey, Stuart R Cobb, Steven J Gray
Intravenous administration of adeno-associated virus serotype 9 (AAV9)/hMECP2 has been shown to extend the lifespan of Mecp2(-/y) mice, but this delivery route induces liver toxicity in wild-type (WT) mice. To reduce peripheral transgene expression, we explored the safety and efficacy of AAV9/hMECP2 injected into the cisterna magna (ICM). AAV9/hMECP2 (1 × 10(12) viral genomes [vg]; ICM) extended Mecp2(-/y) survival but aggravated hindlimb clasping and abnormal gait phenotypes. In WT mice, 1 × 10(12) vg of AAV9/hMECP2 induced clasping and abnormal gait...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28468936/solving-the-puzzle-of-neurological-diseases-an-interview-with-huda-zoghbi
#11
Huda Y Zoghbi
Huda Zoghbi's achievements in the field of neurology are internationally acclaimed. She is best known for elucidating the genetic basis of two complex neurological disorders, spinocerebellar ataxia type 1 and Rett syndrome, and has been honored with many prizes, including The Shaw Prize in Life Science and Medicine in 2016 and the 2017 Breakthrough Prize for Life Sciences. A diligent and creative research scientist at the bench, a respected lab mentor and founding Director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, her inspiration has always been the burning need to help patients faced with devastating neurological problems...
May 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28465761/autonomic-breathing-abnormalities-in-rett-syndrome-caregiver-perspectives-in-an-international-database-study
#12
Jessica Mackay, Jenny Downs, Kingsley Wong, Jane Heyworth, Amy Epstein, Helen Leonard
BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder associated with mutations in the MECP2 gene. Irregular breathing patterns and abdominal bloating are prominent but poorly understood features. Our aims were to characterize the abnormal breathing patterns and abdominal bloating, investigate the distribution of these by age and mutation type and examine their impact and management from a caregiver perspective. METHODS: We invited previously recruited families from the International Rett Syndrome Study to complete a web-based questionnaire concerning their family member with Rett syndrome aged between 2 and 57 years...
2017: Journal of Neurodevelopmental Disorders
https://www.readbyqxmd.com/read/28459435/brown-adipose-tissue-macrophages-control-tissue-innervation-and-homeostatic-energy-expenditure
#13
Yochai Wolf, Sigalit Boura-Halfon, Nina Cortese, Zhana Haimon, Hadas Sar Shalom, Yael Kuperman, Vyacheslav Kalchenko, Alexander Brandis, Eyal David, Yifat Segal-Hayoun, Louise Chappell-Maor, Avraham Yaron, Steffen Jung
Tissue macrophages provide immunological defense and contribute to the establishment and maintenance of tissue homeostasis. Here we used constitutive and inducible mutagenesis to delete the nuclear transcription regulator Mecp2 in macrophages. Mice that lacked the gene encoding Mecp2, which is associated with Rett syndrome, in macrophages did not show signs of neurodevelopmental disorder but displayed spontaneous obesity, which was linked to impaired function of brown adipose tissue (BAT). Specifically, mutagenesis of a BAT-resident Cx3Cr1(+) macrophage subpopulation compromised homeostatic thermogenesis but not acute, cold-induced thermogenesis...
June 2017: Nature Immunology
https://www.readbyqxmd.com/read/28450074/structural-basis-of-mecp2-distribution-on-non-cpg-methylated-and-hydroxymethylated-dna
#14
M Jeannette Sperlazza, Stephanie M Bilinovich, Leander M Sinanan, Fatima R Javier, David C Williams
The Rett-syndrome-associated methyl-CpG-binding protein 2 (MeCP2) selectively binds methylated DNA to regulate transcription during the development of mature neurons. Like other members of the methyl-CpG-binding domain (MBD) family, MeCP2 functions through the recognition of symmetrical 5-methylcytosines in CpG (mCG) dinucleotides. Advances in base-level resolution epigenetic mapping techniques have revealed, however, that MeCP2 can bind asymmetrically methylated and hydroxymethylated CpA dinucleotides and that this alternative binding selectivity modifies gene expression in the developing mammalian brain...
April 24, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28447035/novel-therapeutic-approaches-rett-syndrome-and-human-induced-pluripotent-stem-cell-technology
#15
REVIEW
Mohan Gomathi, Vellingiri Balachandar
Recent advances in induced pluripotent stem cell (iPSC) technology target screening and discovering of therapeutic agents for the possible cure of human diseases. Human induced pluripotent stem cells (hiPSC) are the right kind of platform for testing potency of specific active compounds. Ayurveda, the Indian traditional system of medicine developed between 2,500 and 500 BC, is a science involving the intelligent formulations of herbs and minerals. It can serve as a "goldmine" for novel neuroprotective agents used for centuries to treat neurological disorders...
2017: Stem Cell Investigation
https://www.readbyqxmd.com/read/28439102/mecp2-regulated-mirnas-control-early-human-neurogenesis-through-differential-effects-on-erk-and-akt-signaling
#16
N Mellios, D A Feldman, S D Sheridan, J P K Ip, S Kwok, S K Amoah, B Rosen, B A Rodriguez, B Crawford, R Swaminathan, S Chou, Y Li, M Ziats, C Ernst, R Jaenisch, S J Haggarty, M Sur
Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder caused primarily by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a multifunctional epigenetic regulator with known links to a wide spectrum of neuropsychiatric disorders. Although postnatal functions of MeCP2 have been thoroughly investigated, its role in prenatal brain development remains poorly understood. Given the well-established importance of microRNAs (miRNAs) in neurogenesis, we employed isogenic human RTT patient-derived induced pluripotent stem cell (iPSC) and MeCP2 short hairpin RNA knockdown approaches to identify novel MeCP2-regulated miRNAs enriched during early human neuronal development...
April 25, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28419872/stimulation-of-the-brain-serotonin-receptor-7-rescues-mitochondrial-dysfunction-in-female-mice-from-two-models-of-rett-syndrome
#17
Daniela Valenti, Lidia de Bari, Daniele Vigli, Enza Lacivita, Marcello Leopoldo, Giovanni Laviola, Rosa Anna Vacca, Bianca De Filippis
Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that neurobehavioral and brain molecular alterations can be rescued in a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family, crucially involved in the regulation of brain structural plasticity and cognitive processes, can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective agonist...
April 15, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28399682/clinical-molecular-and-computational-analysis-in-patients-with-a-novel-double-mutation-and-a-new-synonymous-variant-in-mecp2-report-of-the-first-missense-mutation-within-the-at-hook1-cluster-in-rett-syndrome
#18
Marwa Kharrat, Yosra Kamoun, Fatma Kamoun, Emna Ellouze, Marwa Maalej, Nourhene Fendri-Kriaa, Leila Ammar-Keskes, Neila Belghith, Ali Gargouri, Chahnez Triki, Faiza Fakhfakh
Rett syndrome is an X-linked neurodevelopmental disorder, primarily caused by MECP2 mutations. In this study, clinical, molecular and bioinformatics analyses were performed in Rett patients to understand the relationship between MECP2 mutation type and the clinical severity. Two double MeCP2 mutations were detected: a novel one (p.G185 V in cis with p.R255X) in P1 and a known one (p.P179 S in cis with p.R255X) in P2. Besides, a novel synonymous mutation (c.807C>T; p.G269G), which could affect mRNA splicing, was identified in P3...
January 1, 2017: Journal of Child Neurology
https://www.readbyqxmd.com/read/28395743/generation-of-a-clonal-induced-pluripotent-stem-cell-ipsc-line-expressing-the-mutant-mecp2-allele-from-a-rett-syndrome-patient-fibroblast-line
#19
Lisa Hunihan, Jeffrey Brown, Angela Cacace, Alda Fernandes, Andrea Weston
Human fibroblast cells collected from a 3-year old, female Rett Syndrome patient with a 32bp deletion in the X-linked MECP2 gene were obtained from the Coriell Institute. Fibroblasts were reprogrammed to iPSC cells using a Sendai-virus delivery system expressing human KOSM transcription factors. Cell-line pluripotency was demonstrated by gene expression, immunocytochemistry, in-vitro differentiation trilineage capacity and was of normal karyotype. Interestingly, subsequent clones retained the epigenetic memory of the parent fibroblasts allowing for the segregation of wild-type and mutant expressing clones...
April 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28394482/familial-cases-and-male-cases-with-mecp2-mutations
#20
Qingping Zhang, Ying Zhao, Xinhua Bao, Jinjun Luo, Xiaoying Zhang, Jiarui Li, Liping Wei, Xiru Wu
This is the first report of Chinese familial cases with Rett syndrome (RTT) or X-linked mental retardation (XLMR). RTT is a neurodevelopmental disorder that almost exclusively affects females. Most RTT cases are sporadic. We have studied eight cases with MECP2 mutations in six Chinese families, including three females and five males with RTT or XLMR. All shared identical MECP2 mutations with their mothers. The three females fulfilled the diagnostic criteria for RTT, while the five males were XLMR. A random X-chromosome inactive (XCI) pattern was seen in all the three female patients and two mothers while a skewed XCI in the rest four mothers...
April 10, 2017: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
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