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Stem Cell Research Jun 2024Rett syndrome is characterized by severe global developmental impairments with autistic features and loss of purposeful hand skills. Here we show that human induced...
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.
Topics: Rett Syndrome; Humans; Induced Pluripotent Stem Cells; Methyl-CpG-Binding Protein 2; Female; Mutation; Cell Line; Cell Differentiation
PubMed: 38703668
DOI: 10.1016/j.scr.2024.103432 -
Neuron Jun 2024Mutations in the methyl-DNA-binding protein MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). How MECP2 contributes to transcriptional regulation in...
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). MECP2 directly interacts with RNA Pol II, and genes occupied by both proteins showed reduced expression in neurons with MECP2 patient mutations. We conclude that MECP2 acts as a positive cofactor for RNA Pol II gene expression at many neuronal genes that harbor CpG islands in promoter-proximal regions and that RTT is due, in part, to the loss of gene activity of these genes in neurons.
Topics: RNA Polymerase II; Methyl-CpG-Binding Protein 2; Humans; Neurons; Transcription, Genetic; Promoter Regions, Genetic; Rett Syndrome; CpG Islands; Mutation; Gene Expression Regulation
PubMed: 38697112
DOI: 10.1016/j.neuron.2024.04.007 -
Annals of Medicine and Surgery (2012) May 2024
PubMed: 38694380
DOI: 10.1097/MS9.0000000000001896 -
Sleep Medicine Jul 2024Rett syndrome (RTT) is a rare neurological disorder primarily associated with mutations in the methyl-CpG-binding protein 2 (MECP2) gene. The syndrome is characterized...
BACKGROUND
Rett syndrome (RTT) is a rare neurological disorder primarily associated with mutations in the methyl-CpG-binding protein 2 (MECP2) gene. The syndrome is characterized by cognitive, social, and physical impairments, as well as sleep disorders and epilepsy. Notably, dysfunction of the autonomic nervous system is a key feature of the syndrome. Although Heart Rate Variability (HRV) has been used to investigate autonomic nervous system dysfunction in RTT during wakefulness, there is still a significant lack of information regarding the same during sleep. Therefore, our aim was to investigate cardiovascular autonomic modulation during sleep in subjects with RTT compared to an age-matched healthy control group (HC).
METHOD
A complete overnight polysomnographic (PSG) recording was obtained from 11 patients with Rett syndrome (all females, 10 ± 4 years old) and 11 HC (all females, 11 ± 4 years old; p = 0.48). Electrocardiogram and breathing data were extracted from PSG and divided into wake, non-REM, and REM sleep stages. Cardiac autonomic control was assessed using symbolic non-linear heart rate variability analysis. The symbolic analysis identified three patterns: 0 V% (sympathetic), 2UV%, and 2LV% (vagal).
RESULTS
The 0 V% was higher in the RTT group than in the HC group during wake, non-REM, and REM stages (p < 0.01), while the 2LV and 2UV% were lower during wake and sleep stages (p < 0.01). However, the 0 V% increased similarly from the wake to the REM stage in both RTT and HC groups.
CONCLUSIONS
Therefore, the sympatho-vagal balance shifted towards sympathetic predominance and vagal withdrawal during wake and sleep in RTT, although cardiac autonomic dynamics were preserved during sleep.
Topics: Humans; Rett Syndrome; Female; Polysomnography; Heart Rate; Child; Wakefulness; Adolescent; Sympathetic Nervous System; Electrocardiography; Sleep; Sleep Stages; Heart
PubMed: 38692221
DOI: 10.1016/j.sleep.2024.04.036 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... May 2024To explore the genetic characteristics of a child with comorbid 16p11.2 microdeletion syndrome and Rett syndrome (RTT).
OBJECTIVE
To explore the genetic characteristics of a child with comorbid 16p11.2 microdeletion syndrome and Rett syndrome (RTT).
METHODS
A male infant who was admitted to Gansu Provincial Maternity and Child Health Care Hospital in May 2020 was selected as the study subject. Clinical data of the infant was collected. Genomic DNA was extracted from peripheral blood samples from the infant and his parents, and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing.
RESULTS
The patient, a 4-day-old male infant, had presented with poor response, poor intake, feeding difficulties, and deceased at 8 months after birth. WES revealed that he has harbored a 0.643 Mb deletion in the 16p11.2 region, which encompassed key genes of the 16p11.2 microdeletion syndrome such as ALDOA, CORO1A, KIFF22, PRRT2 and TBX6. His father has carried the same deletion, but was phenotypically normal. The deletion was predicted to be pathogenic. The child was also found to harbor a maternally derived c.763C>T (p.R255X) hemizygous variant of the MECP2 gene, which was also predicted to be pathogenic (PVS1+PS4+PM2_Supporting).
CONCLUSION
The 16p11.2 deletion and the MECP2: c.763C>T (p.R255X) variant probably underlay the pathogenesis in this infant.
Topics: Humans; Infant, Newborn; Male; Autistic Disorder; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 16; Exome Sequencing; Intellectual Disability; Methyl-CpG-Binding Protein 2; Rett Syndrome
PubMed: 38684311
DOI: 10.3760/cma.j.cn511374-20230403-00185 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... May 2024To carry out preimplantation genetic testing (PGT) for a Chinese pedigree affected with Rett syndrome (RTT).
OBJECTIVE
To carry out preimplantation genetic testing (PGT) for a Chinese pedigree affected with Rett syndrome (RTT).
METHODS
A pedigree affected with RTT who had presented at the First Hospital of Jilin University on June 4, 2021 was selected as the study subject. Variant of the MECP2 gene was analyzed by next generation sequencing (NGS) and Sanger sequencing. Direct sequencing was also used to determine the carrier status for the c.925C>T variant of the MECP2 gene in the blastocysts, and Sanger sequencing was used to validate the results. The MECP2 gene and 168 effective single nucleotide polymorphism (SNP) loci within 2 Mb ranges up- and downstream of the gene were used to construct a haplotype for analyzing the variant site in the embryos, and embryos without the variant were subjected to the analysis for chromosomal aneuploidies.
RESULTS
PGT analysis revealed that five out of seven blastocysts did not harbor the pathogenic variant. The results of aneuploidy analysis indicated that two out of five blastocysts without the variant were euploid. Following genetic counselling, the couple had opted to transplant the optimal blastocyst. Following clinical pregnancy, prenatal diagnosis showed that the fetus has a normal chromosomal karyotype, and the c.925C>T variant was not detected in the amniotic fluid sample. A healthy girl was born by Cesarean section at full term.
CONCLUSION
NGS can attain efficient PGT detection and reduce the risk of disease recurrence in families affected with RTT.
Topics: Adult; Female; Humans; Pregnancy; East Asian People; Genetic Testing; High-Throughput Nucleotide Sequencing; Methyl-CpG-Binding Protein 2; Pedigree; Polymorphism, Single Nucleotide; Preimplantation Diagnosis; Rett Syndrome
PubMed: 38684295
DOI: 10.3760/cma.j.cn511734-20230313-00127 -
Epilepsy & Behavior Reports 2024Contextual events are recognized to affect seizure-like behaviors, yet there is limited research on procedures assessing contextual control. This study aimed to examine...
Contextual events are recognized to affect seizure-like behaviors, yet there is limited research on procedures assessing contextual control. This study aimed to examine the utilization of a brief experimental precursor functional analysis within a clinical team assessment. Furthermore, the study explored if telehealth supervision could guide a parent administered replication of the functional analysis. The participants were a young female with Rett syndrome and a history of epilepsy as well as non-epileptic seizures and her mother. The functional analysis procedures consisted of the systematic alternations of contextual conditions that were hypothesized to either prevent or evoke seizure-like behaviors. The primary outcome measure was the occurrence of behavioral precursors that were identified to consequently signal subsequent seizure-like behaviors. In addition, procedure fidelity and interobserver agreement data were obtained alongside parent rating of the procedure's social validity. The clinical functional analysis clearly suggested that the seizure-like behaviors served the function of access to attention and preferred activities. A parent administered functional analysis replicated clinical functional analysis findings. The parent's fidelity to procedures was high and scores in social validity were excellent. The results show that functional analysis procedures could provide essential information in assessment of non-epileptic seizures. Strengths and limitations are discussed.
PubMed: 38681818
DOI: 10.1016/j.ebr.2024.100666 -
Pediatric Neurology Jul 2024
Topics: Humans; Neurodevelopmental Disorders; Nuclear Receptor Co-Repressor 2
PubMed: 38677047
DOI: 10.1016/j.pediatrneurol.2024.04.003 -
Biomolecules Apr 2024Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that...
Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental disability. Rett Syndrome is also associated with metabolic abnormalities, and the anti-diabetic drug metformin is suggested to be a potential drug of choice with low or no side-effects. Previously, we showed that exposure of metformin in a human brain cell line induces transcripts, the dominant isoform of the gene in the brain, mutations in which causes RTT. Here, we report the molecular impact of metformin in mice. Protein analysis of specific brain regions in the male and female mice by immunoblotting indicated that metformin induces MeCP2 in the hippocampus, in a sex-dependent manner. Additional experiments confirm that the regulatory role of metformin on the MeCP2 target "BDNF" is brain region-dependent and sex-specific. Measurement of the ribosomal protein S6 (in both phosphorylated and unphosphorylated forms) confirms the sex-dependent role of metformin in the liver. Our results can help foster a better understanding of the molecular impact of metformin in different brain regions of male and female adult mice, while providing some insight towards its potential in therapeutic strategies for the treatment of Rett Syndrome.
Topics: Animals; Female; Male; Mice; Brain; Brain-Derived Neurotrophic Factor; Hippocampus; Metformin; Methyl-CpG-Binding Protein 2; Mice, Inbred C57BL; Phosphorylation; Rett Syndrome; Ribosomal Protein S6; Sex Characteristics; Sex Factors
PubMed: 38672521
DOI: 10.3390/biom14040505 -
Molecular and Cellular Neurosciences Jun 2024Astrocytes are in constant communication with neurons during the establishment and maturation of functional networks in the developing brain. Astrocytes release...
Astrocytes are in constant communication with neurons during the establishment and maturation of functional networks in the developing brain. Astrocytes release extracellular vesicles (EVs) containing microRNA (miRNA) cargo that regulates transcript stability in recipient cells. Astrocyte released factors are thought to be involved in neurodevelopmental disorders. Healthy astrocytes partially rescue Rett Syndrome (RTT) neuron function. EVs isolated from stem cell progeny also correct aspects of RTT. EVs cross the blood-brain barrier (BBB) and their cargo is found in peripheral blood which may allow non-invasive detection of EV cargo as biomarkers produced by healthy astrocytes. Here we characterize miRNA cargo and sequence motifs in healthy human astrocyte derived EVs (ADEVs). First, human induced Pluripotent Stem Cells (iPSC) were differentiated into Neural Progenitor Cells (NPCs) and subsequently into astrocytes using a rapid differentiation protocol. iPSC derived astrocytes expressed specific markers, displayed intracellular calcium transients and secreted ADEVs. miRNAs were identified by RNA-Seq on astrocytes and ADEVs and target gene pathway analysis detected brain and immune related terms. The miRNA profile was consistent with astrocyte identity, and included approximately 80 miRNAs found in astrocytes that were relatively depleted in ADEVs suggestive of passive loading. About 120 miRNAs were relatively enriched in ADEVs and motif analysis discovered binding sites for RNA binding proteins FUS, SRSF7 and CELF5. miR-483-5p was the most significantly enriched in ADEVs. This miRNA regulates MECP2 expression in neurons and has been found differentially expressed in blood samples from RTT patients. Our results identify potential miRNA biomarkers selectively sorted into ADEVs and implicate RNA binding protein sequence dependent mechanisms for miRNA cargo loading.
Topics: Humans; Extracellular Vesicles; Induced Pluripotent Stem Cells; MicroRNAs; Astrocytes; Neurons; Cell Differentiation; Cells, Cultured; Neural Stem Cells
PubMed: 38663691
DOI: 10.1016/j.mcn.2024.103933