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JOURNAL ARTICLE
Junye Ge, Shengjun Xie, Jiamei Duan, Biqing Tian, Pengfei Ren, Erling Hu, Qiyi Huang, Honghui Mao, Yuxin Zou, Qian Chen, Wenting Wang
OBJECTIVE: Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2Tg1 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus...
May 31, 2024: Epilepsia
#2
JOURNAL ARTICLE
Valeria Cordone
To date, Rett syndrome (RTT), a genetic disorder mainly caused by mutations in the X-linked MECP2 gene, is increasingly considered a broad-spectrum pathology, instead of just a neurodevelopmental disease, due to the multitude of peripheral co-morbidities and the compromised metabolic pathways, affecting the patients. The altered molecular processes include an impaired mitochondrial function, a perturbed redox homeostasis, a chronic subclinical inflammation and an improper cholesterol metabolism. The persistent subclinical inflammatory condition was first defined ten years ago, as a previously unrecognized feature of RTT, playing a role in the pathology progress and modulation of phenotypical severity...
May 28, 2024: Archives of Biochemistry and Biophysics
#3
Boris Kantor, Bernadette Odonovan, Joseph Rittiner, Dellila Hodgson, Nicholas Lindner, Sophia Guerrero, Wendy Dong, Austin Zhang, Ornit Chiba-Falek
Safely and efficiently controlling gene expression is a long-standing goal of biomedical research, and the recently discovered bacterial CRISPR/Cas system can be harnessed to create powerful tools for epigenetic editing. Current state-of-the-art systems consist of a deactivated-Cas9 nuclease (dCas9) fused to one of several epigenetic effector motifs/domains, along with a guide RNA (gRNA) which defines the genomic target. Such systems have been used to safely and effectively silence or activate a specific gene target under a variety of circumstances...
May 19, 2024: bioRxiv
#4
Osman Sharifi, Viktoria Haghani, Kari E Neier, Keith J Fraga, Ian Korf, Sophia M Hakam, Gerald Quon, Nelson Johansen, Dag H Yasui, Janine M LaSalle
Dominant X-linked diseases are uncommon due to female X chromosome inactivation (XCI). While random XCI usually protects females against X-linked mutations, Rett syndrome (RTT) is a female neurodevelopmental disorder caused by heterozygous MECP2 mutation. After 6-18 months of typical neurodevelopment, RTT girls undergo poorly understood regression. We performed longitudinal snRNA-seq on cerebral cortex in a construct-relevant Mecp2e1 mutant mouse model of RTT, revealing transcriptional effects of cell type, mosaicism, and sex on progressive disease phenotypes...
May 19, 2024: bioRxiv
#5
JOURNAL ARTICLE
María Galán-Olleros, Elena González-Alguacil, Víctor Soto-Insuga, María Teresa Vara-Arias, Nelmar Valentina Ortiz-Cabrera, J Ignacio Serrano, Rosa M Egea-Gámez, Juan José García-Peñas, Ignacio Martínez-Caballero
PURPOSE: Rett syndrome (RTT) is a rare multi-systemic disorder primarily linked to mutations in MECP2 gene. This study aims to describe the prevalence of orthopedic conditions in RTT patients, and examine their intricate interplay with functional capabilities, and MECP2 variant subtypes. METHODS: Conducted as a cross-sectional retrospective observational study, the research encompassed 55 patients meeting clinical RTT criteria and holding MECP2 mutations. A review of clinical records was performed to gather demographic data, mutation subtypes, orthopedic conditions, management strategies, and assessments of function...
May 25, 2024: Journal of Autism and Developmental Disorders
#6
REVIEW
Martin L Pall
The roles of perinatal development, intracellular calcium [Ca2+ ]i, and synaptogenesis disruption are not novel in the autism/ASD literature. The focus on six mechanisms controlling synaptogenesis, each regulated by [Ca2+ ]i, and each aberrant in ASDs is novel. The model presented here predicts that autism epidemic causation involves central roles of both electromagnetic fields (EMFs) and chemicals. EMFs act via voltage-gated calcium channel (VGCC) activation and [Ca2+ ]i elevation. A total of 15 autism-implicated chemical classes each act to produce [Ca2+ ]i elevation, 12 acting via NMDA receptor activation, and three acting via other mechanisms...
April 30, 2024: Brain Sciences
#7
JOURNAL ARTICLE
Jonathan K Merritt, Xiaolan Fang, Raymond C Caylor, Steven A Skinner, Michael J Friez, Alan K Percy, Jeffrey L Neul
Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene Methyl-CpG Binding Protein 2 ( MECP2 ). Most often, the disease causing the MECP2 allele resides on the paternal X chromosome while a healthy copy is maintained on the maternal X chromosome with inactivation (XCI), resulting in mosaic expression of one allele in each cell. Preferential inactivation of the paternal X chromosome is theorized to result in reduced disease severity; however, establishing such a correlation is complicated by known MECP2 genotype effects and an age-dependent increase in severity...
May 8, 2024: Genes
#8
JOURNAL ARTICLE
Destynie Medeiros, Karen Ayala-Baylon, Hailey Egido-Betancourt, Eric Miller, Christopher Chapleau, Holly Robinson, Mary L Phillips, Tao Yang, Frank M Longo, Wei Li, Lucas Pozzo-Miller
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice...
June 1, 2024: Disease Models & Mechanisms
#9
JOURNAL ARTICLE
Alistair T Pagnamenta, Jing Yu, Susan Walker, Alexandra J Noble, Jenny Lord, Prasun Dutta, Mona Hashim, Carme Camps, Hannah Green, Smrithi Devaiah, Lina Nashef, Jason Parr, Carl Fratter, Rana Ibnouf Hussein, Sarah J Lindsay, Fiona Lalloo, Benito Banos-Pinero, David Evans, Lucy Mallin, Adrian Waite, Julie Evans, Andrew Newman, Zoe Allen, Cristina Perez-Becerril, Gavin Ryan, Rachel Hart, John Taylor, Tina Bedenham, Emma Clement, Ed Blair, Eleanor Hay, Francesca Forzano, Jenny Higgs, Natalie Canham, Anirban Majumdar, Meriel McEntagart, Nayana Lahiri, Helen Stewart, Sarah Smithson, Eduardo Calpena, Adam Jackson, Siddharth Banka, Hannah Titheradge, Ruth McGowan, Julia Rankin, Charles Shaw-Smith, D Gareth Evans, George J Burghel, Miriam J Smith, Emily Anderson, Rajesh Madhu, Helen Firth, Sian Ellard, Paul Brennan, Claire Anderson, Doug Taupin, Mark T Rogers, Jackie A Cook, Miranda Durkie, James E East, Darren Fowler, Louise Wilson, Rebecca Igbokwe, Alice Gardham, Ian Tomlinson, Diana Baralle, Holm H Uhlig, Jenny C Taylor
Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo)...
May 16, 2024: American Journal of Human Genetics
#10
REVIEW
Mohamed Abo Zeid, Amr Elrosasy, Rashad G Mohamed, Alina Ghazou, Elarbi Goufa, Nourhan Hassan, Yasmine Abuzaid
BACKGROUND: Rett syndrome (RTT) is an uncommon inherited neurodevelopmental disorder that affects brain development, mostly in females. It results from mutation in MECP2 gene in the long arm (q) of the X chromosome. OBJECTIVE: Trofinetide is a recently developed drug that has a neuroprotective effect on neurons, and it is our aim in this meta-analysis to evaluate its efficacy and safety in treating Rett syndrome patients. METHODS: We searched 5 databases (PubMed, Scopus, Embase, Web of Science, and Cochrane Library databases) to identify randomized controlled trials (RCTs) comparing Trofinetide and placebo in patients with Rett syndrome until August 13, 2023...
May 21, 2024: Neurological Sciences
#11
JOURNAL ARTICLE
Jun Yang, Shitian Zou, Zeyou Qiu, Mingqiang Lai, Qing Long, Huan Chen, Ping Lin Lai, Sheng Zhang, Zhi Rao, Xiaoling Xie, Yan Gong, Anling Liu, Mangmang Li, Xiaochun Bai
Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry...
May 15, 2024: ELife
#12
JOURNAL ARTICLE
Ainhoa Pascual-Alonso, Clara Xiol, Dmitrii Smirnov, Rober Kopajtich, Holger Prokisch, Judith Armstrong
MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by the gain of dose of at least the genes MECP2 and IRAK1 and is characterised by intellectual disability (ID), developmental delay, hypotonia, epilepsy and recurrent infections. It mainly affects males, and females can be affected or asymptomatic carriers. Rett syndrome (RTT) is mainly triggered by loss of function mutations in MECP2 and is a well described syndrome that presents ID, epilepsy, lack of purposeful hand use and impaired speech, among others...
May 15, 2024: European Journal of Neuroscience
#13
Nicole Maurici, Tien M Phan, Jessica L Henty-Ridilla, Young C Kim, Jeetain Mittal, Alaji Bah
Chromatin organization controls DNA's accessibility to regulatory factors to influence gene expression. Heterochromatin, or transcriptionally silent chromatin enriched in methylated DNA and methylated histone tails, self-assembles through multivalent interactions with its associated proteins into a condensed, but dynamic state. Liquid-liquid phase separation (LLPS) of key heterochromatin regulators, such as heterochromatin protein 1 (HP1), plays an essential role in heterochromatin assembly and function. Methyl-CpG-binding protein 2 (MeCP2), the most studied member of the methyl-CpG-binding domain (MBD) family of proteins, has been recently shown to undergo LLPS in the absence and presence of methylated DNA...
April 29, 2024: bioRxiv
#14
JOURNAL ARTICLE
Himani Adarsh, Namita Sharma, Akhilesh Sharma, Sankie Swer, Shubh Mohan Singh
No abstract text is available yet for this article.
March 2024: Indian Journal of Psychological Medicine
#15
REVIEW
Indumathy Jagadeeswaran, Jiyoung Oh, Sarah E Sinnett
BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). After gene transfer in mice, exogenous MeCP2 expression must be regulated to avoid dose-dependent toxicity. SUMMARY: The preclinical gene therapy literature for treating Rett syndrome (RTT) illustrates a duly diligent progression that begins with proof-of-concept studies and advances toward the development of safer, regulated MECP2 viral genome designs...
May 9, 2024: Developmental Neuroscience
#16
JOURNAL ARTICLE
Zurui Li, Bingwa Fang, Pengcheng Dong, Wenjuan Shan
The Yarkand hare (Lepus yarkandensis) inhabits arid desert areas and is endemic to China. It has evolved various adaptations to survive in hot arid environments, including stress responses, the ability to maintain water homeostasis and heat tolerance. Here, we performed a selective sweep analysis to identify the candidate genes for adaptation to hot arid environments in the Yarkand hare. A total of 397 237 single-nucleotide polymorphisms were obtained from 80 Yarkand hares, which inhabit hot arid environments, and 36 Tolai hares (Lepus tolai), which inhabit environments with a mild climate, via specific-locus amplified fragment sequencing...
May 9, 2024: Animal Genetics
#17
JOURNAL ARTICLE
Raphaël Pantier, Megan Brown, Sicheng Han, Katie Paton, Stephen Meek, Thomas Montavon, Nicholas Shukeir, Toni McHugh, David A Kelly, Tino Hochepied, Claude Libert, Thomas Jenuwein, Tom Burdon, Adrian Bird
Correlative evidence has suggested that the methyl-CpG-binding protein MeCP2 contributes to the formation of heterochromatin condensates via liquid-liquid phase separation. This interpretation has been reinforced by the observation that heterochromatin, DNA methylation and MeCP2 co-localise within prominent foci in mouse cells. The findings presented here revise this view. MeCP2 localisation is independent of heterochromatin as MeCP2 foci persist even when heterochromatin organisation is disrupted. Additionally, MeCP2 foci fail to show hallmarks of phase separation in live cells...
May 8, 2024: Nature Communications
#18
JOURNAL ARTICLE
Ting Peng, Jiayan Cui, Ziyun Ni, Yao Tang, Xiaojing Cao, Sihan Li, Xixi Cheng, Jin Huang
Persistent and intense uterine contraction is a risk factor for preterm labor. We previously found that Methyl-CpG binding protein 2 (MeCP2), as a target of infection-related microRNA miR-212-3p, may play an inhibitory role in regulating myometrium contraction. However, the molecular mechanisms by which MeCP2 regulates myometrial contraction are still unknown. In this study, we found that MeCP2 protein expression was lower in myometrial specimens obtained from preterm labor cases, compared to those obtained from term labor cases...
May 4, 2024: Molecular Human Reproduction
#19
JOURNAL ARTICLE
Miyu Mori, Shoko Yoshii, Michiya Noguchi, Daigo Takagi, Tomoya Shimizu, Hidenori Ito, Mami Matsuo-Takasaki, Yukio Nakamura, Satoru Takahashi, Hiromichi Hamada, Kiyoshi Ohnuma, Tadashi Shiohama, Yohei Hayashi
Rett syndrome is characterized by severe global developmental impairments with autistic features and loss of purposeful hand skills. Here we show that human induced pluripotent stem cell (hiPSC) lines derived from four Japanese female patients with Rett syndrome are generated from peripheral blood mononuclear cells using Sendai virus vectors. The generated hiPSC lines showed self-renewal and pluripotency and carried heterozygous frameshift, missense, or nonsense mutations in the MECP2 gene. Since the molecular pathogenesis caused by MECP2 dysfunction remains unclear, these cell resources are useful tools to establish disease models and develop new therapies for Rett syndrome...
May 1, 2024: Stem Cell Research
#20
JOURNAL ARTICLE
Yi Liu, Anthony Flamier, George W Bell, Annette Jun Diao, Troy W Whitfield, Hao-Che Wang, Yizhe Wu, Fabian Schulte, Max Friesen, Ruisi Guo, Maisam Mitalipova, X Shawn Liu, Seychelle M Vos, Richard A Young, Rudolf Jaenisch
Mutations in the methyl-DNA-binding protein MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). How MECP2 contributes to transcriptional regulation in normal and disease states is unresolved; it has been reported to be an activator and a repressor. We describe here the first integrated CUT&Tag, transcriptome, and proteome analyses using human neurons with wild-type (WT) and mutant MECP2 molecules. MECP2 occupies CpG-rich promoter-proximal regions in over four thousand genes in human neurons, including a plethora of autism risk genes, together with RNA polymerase II (RNA Pol II)...
April 30, 2024: Neuron
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