Reversal of MECP2 duplication syndrome using genetic rescue and antisense oligonucleotides
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE71235 | GEO | 2015/11/27
SECONDARY ACCESSION(S): PRJNA290638
REPOSITORIES: GEO
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Project description:MECP2 duplication syndrome, a childhood neurological disorder characterized by autism, intellectual disability, motor dysfunction, anxiety and epilepsy, is caused by a duplication on chromosome Xq28 spanning the MECP2 gene that results in doubling of MeCP2 levels. MECP2 overexpression in mice causes neurobehavioral and electroencephalographic defects similar to those of human patients, but the gross anatomy of the brain remains unaffected. We hypothesized that MECP2 duplication syndrome would be reversible and tested two methods to restore MeCP2 levels to normal: conditional genetic recombination and antisense oligonucleotide therapy. Both approaches rescued molecular, physiological and behavioral features of adult symptomatic mice. Antisense therapy also restored normal MeCP2 levels in lymphoblastoid cells from MECP2 duplication patients, in a dose-dependent manner. Our data indicate that antisense oligonucleotides could provide a viable therapeutic approach for human MECP2 duplication syndrome as well as other disorders involving copy number gains.
2015-11-27 | GSE71229 | GEO
Project description:Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders. MECP2 duplication syndrome is one of the most common genomic rearrangements in males and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death. The broad range of deficits caused by methyl-CpG-binding protein 2 (MeCP2) overexpression poses a daunting challenge to traditional biochemical-pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MeCP2 and are amenable to translation into clinical therapy. The first question that we addressed was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders, including loss of MeCP2 in Rett syndrome, indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional Mecp2-overexpressing mouse model, here we show that correction of MeCP2 levels largely reverses the behavioural, molecular and electrophysiological deficits. We also reduced MeCP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with messenger RNA transcribed from a target gene and silence it, and have been successfully used to correct deficits in different mouse models. We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult symptomatic transgenic MECP2 duplication mice (MECP2-TG), and corrected MECP2 levels in lymphoblastoid cells from MECP2 duplication patients in a dose-dependent manner.
| S-EPMC4839300 | biostudies-literature
Project description:MECP2 duplication syndrome, a childhood neurological disorder characterized by autism, intellectual disability, motor dysfunction, anxiety and epilepsy, is caused by a duplication on chromosome Xq28 spanning the MECP2 gene that results in doubling of MeCP2 levels. MECP2 overexpression in mice causes neurobehavioral and electroencephalographic defects similar to those of human patients, but the gross anatomy of the brain remains unaffected. We hypothesized that MECP2 duplication syndrome would be reversible and tested two methods to restore MeCP2 levels to normal: conditional genetic recombination and antisense oligonucleotide therapy. Both approaches rescued molecular, physiological and behavioral features of adult symptomatic mice. Antisense therapy also restored normal MeCP2 levels in lymphoblastoid cells from MECP2 duplication patients, in a dose-dependent manner. Our data indicate that antisense oligonucleotides could provide a viable therapeutic approach for human MECP2 duplication syndrome as well as other disorders involving copy number gains.
2015-11-27 | GSE71234 | GEO
Project description:MECP2 duplication syndrome, a childhood neurological disorder characterized by autism, intellectual disability, motor dysfunction, anxiety and epilepsy, is caused by a duplication on chromosome Xq28 spanning the MECP2 gene that results in doubling of MeCP2 levels. MECP2 overexpression in mice causes neurobehavioral and electroencephalographic defects similar to those of human patients, but the gross anatomy of the brain remains unaffected. We hypothesized that MECP2 duplication syndrome would be reversible and tested two methods to restore MeCP2 levels to normal: conditional genetic recombination and antisense oligonucleotide therapy. Both approaches rescued molecular, physiological and behavioral features of adult symptomatic mice. Antisense therapy also restored normal MeCP2 levels in lymphoblastoid cells from MECP2 duplication patients, in a dose-dependent manner. Our data indicate that antisense oligonucleotides could provide a viable therapeutic approach for human MECP2 duplication syndrome as well as other disorders involving copy number gains.
2015-11-27 | GSE71233 | GEO
Project description:In this review, we detail the history, molecular diagnosis, epidemiology, and clinical features of the MECP2 duplication syndrome, including considerations for the care of patients with this X-linked neurodevelopmental disorder. MECP2 duplication syndrome is 100% penetrant in affected males and is associated with infantile hypotonia, severe to profound mental retardation, autism or autistic features, poor speech development, recurrent infections, epilepsy, progressive spasticity, and, in some cases, developmental regression. Most of the reported cases are inherited, however, de novo cases have been documented. While carrier females have been reported to be unaffected, more recent research demonstrates that despite normal intelligence, female carriers display a range of neuropsychiatric phenotypes that pre-date the birth of an affected son. Given what we know of the syndrome to date, we propose that genetic testing is warranted in cases of males with infantile hypotonia and in cases of boys with mental retardation and autistic features with or without recurrent infections, progressive spasticity, epilepsy, or developmental regression. We discuss recommendations for clinical management and surveillance as well as the need for further clinical, genotype-phenotype, and molecular studies to assist the patients and their families who are affected by this syndrome.
| S-EPMC2861792 | biostudies-literature
Project description:Abstract Rett syndrome (RTT) is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in the gene Methyl-CpG-binding protein 2 (MECP2), which encodes the MeCP2 protein. RTT is a MECP2-related disorder, along with MECP2 duplication syndrome (MDS), caused by gain-of-function duplications of MECP2. Nearly two decades of research have advanced our knowledge of MeCP2 function in health and disease. The following review will discuss MeCP2 protein function and its dysregulation in the MECP2-related disorders RTT and MDS. This will include a discussion of the genetic underpinnings of these disorders, specifically how sporadic X-chromosome mutations arise and manifest in specific populations. We will then review current diagnostic guidelines and clinical manifestations of RTT and MDS. Next, we will delve into MeCP2 biology, describing the dual landscapes of methylated DNA and its reader MeCP2 across the neuronal genome as well as the function of MeCP2 as a transcriptional modulator. Following this, we will outline common MECP2 mutations and genotype–phenotype correlations in both diseases, with particular focus on mutations associated with relatively mild disease in RTT. We will also summarize decades of disease modeling and resulting molecular, synaptic, and behavioral phenotypes associated with RTT and MDS. Finally, we list several therapeutics in the development pipeline for RTT and MDS and available evidence of their safety and efficacy.
| S-EPMC9719276 | biostudies-literature
Project description:Increased dosage of methyl-CpG-binding protein-2 (MeCP2) results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSCs) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increased synaptogenesis and dendritic complexity. In addition, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 functions at the epigenetic level, we tested whether these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders.
| S-EPMC4720528 | biostudies-literature
Project description:BackgroundMethyl-CpG-binding protein 2 (MeCP2) is a key transcriptional regulator of gene expression in the maintenance and development of the central nervous system. Loss- or gain-function of this gene may contribute to neurodevelopmental disorders. The aim of this study is to delineate the clinical characteristics of MECP2 duplication syndrome and the hereditary mechanism in a Chinese family.Case presentationWe identified a Chinese family with three persons carry MECP2 gene duplication: a boy, his mother and his grandmother. The duplication segment which was detected by multiplex ligation-dependent probe amplification (MLPA) included gene MECP2, interleukin-1 receptor-associated kinase 1 (IRAK1), filamin A (FLNA), and L1 cell adhesion molecule (L1CAM). Furthermore, array comparative genomic hybridization (aCGH) was performed on the mother, showed that MECP2 containing duplication was 510 Kb (153,113,885-153,624,154), including 16 other genes except MECP2. The boy showed most symptoms of MECP2 duplication syndrome. His mother and maternal grandmother were asymptomatic. Both female carriers had a skewed X chromosome inactivation (XCI), which were 80:20 and 74:26 respectively.ConclusionTo our knowledge, this is the second reported Chinese Han family with MECP2-containing duplications. And this patient had recurrent respiratory infections which was different from the first two Chinese-brother cases. MECP2 is the core gene responsible for MECP2 duplication syndrome. XCI may play an important role in modulating the clinical manifestation.
| S-EPMC4682232 | biostudies-literature
Project description:MECP2 (methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We describe for the first time the detailed infectious and immunological phenotype of MECP2 duplication syndrome. 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria (S.pneumoniae, H.influenzae) were frequently isolated. T-cell immunity showed no gross abnormalities in 14/14 patients and IFNy-secretion upon ConA-stimulation was not decreased in 6/7 patients. In 6/21 patients IgG2-deficiency was detected - in 4/21 patients accompanied by IgA-deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra-normal IgG1-levels were detected in 11/21 patients and supra-normal IgG3-levels were seen in 8/21 patients - in 6 of the patients as combined elevation of IgG1 and IgG3. Three of the four patients with IgA/IgG2-deficiency developed multiple severe infections. Upon infections pronounced acute-phase responses were common: 7/10 patients showed CRP values above 200 mg/l. Our data for the first time show systematically that increased susceptibility to infections in MECP2 duplication syndrome is associated with IgA/IgG2-deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with MECP2 duplication syndrome and low IgA/IgG2 may benefit from prophylactic substitution of sIgA and IgG.
| S-EPMC7101860 | biostudies-literature
Project description:MECP2 duplication syndrome (MDS; OMIM 300260) is an X-linked neurodevelopmental disorder caused by nonrecurrent duplications of the Xq28 region involving the gene methyl-CpG-binding protein 2 (MECP2; OMIM 300005). The core phenotype of affected individuals includes infantile hypotonia, severe intellectual disability, very poor-to-absent speech, progressive spasticity, seizures, and recurrent infections. The condition is 100% penetrant in males, with observed variability in phenotypic expression within and between families. Features of MDS in individuals of African descent are not well known. Here, we describe a male patient from Cameroon, with MDS caused by an inherited 610 kb microduplication of Xq28 encompassing the genes MECP2, IRAK1, L1CAM, and SLC6A8. This report supplements the public data on MDS and contributes by highlighting the phenotype of this condition in affected individuals of African descent.
| S-EPMC7450984 | biostudies-literature