MeCP2_e2 partially compensates for lack of MeCP2_e1: A male case of Rett syndrome

Takeguchi, Ryo; Takahashi, Satoru; Kuroda, Mami; Tanaka, Ryosuke; Suzuki, Nao; Tomonoh, Yuko; Ihara, Yukiko; Sugiyama, Nobuyoshi; Itoh, Masayuki

doi:10.1002/mgg3.1088

Cited by 10 publications

(10 citation statements)

References 17 publications

(18 reference statements)

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“…The extent of overlap observed is, to a certain degree, unsurprising. It has been recently shown that MeCP2-E2 is able to partially compensate for the lack of the E1 isoform in a male case of RTT phenotype ( Takeguchi et al, 2020 ). However, the association of E1 with tubulin remains intriguing.…”

Section: Subsectionsmentioning

confidence: 99%

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021

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Mutations in methyl CpG binding protein 2 (MeCP2) are the major cause of Rett syndrome (RTT), a rare neurodevelopmental disorder with a notable period of developmental regression following apparently normal initial development. Such MeCP2 alterations often result in changes to DNA binding and chromatin clustering ability, and in the stability of this protein. Among other functions, MeCP2 binds to methylated genomic DNA, which represents an important epigenetic mark with broad physiological implications, including neuronal development. In this review, we will summarize the genetic foundations behind RTT, and the variable degrees of protein stability exhibited by MeCP2 and its mutated versions. Also, past and emerging relationships that MeCP2 has with mRNA splicing, miRNA processing, and other non-coding RNAs (ncRNA) will be explored, and we suggest that these molecules could be missing links in understanding the epigenetic consequences incurred from genetic ablation of this important chromatin modifier. Importantly, although MeCP2 is highly expressed in the brain, where it has been most extensively studied, the role of this protein and its alterations in other tissues cannot be ignored and will also be discussed. Finally, the additional complexity to RTT pathology introduced by structural and functional implications of the two MeCP2 isoforms (MeCP2-E1 and MeCP2-E2) will be described. Epigenetic therapeutics are gaining clinical popularity, yet treatment for Rett syndrome is more complicated than would be anticipated for a purely epigenetic disorder, which should be taken into account in future clinical contexts.

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Section: Subsectionsmentioning

confidence: 99%

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021

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“…Although several protein-coding and non-coding MECP2 transcripts have been identified or predicted ( Singh et al, 2008 ), the two most-studied splice variants of MeCP2 are known as MeCP2E1 and MeCP2E2 ( Kriaucionis and Bird, 2004 ; Mnatzakanian et al, 2004 ). Accordingly, MeCP2E1 and E2 isoform-specific expression, regulation, function, and clinical relevance to RTT have been the focus of several research studies ( Rastegar et al, 2009 ; Itoh et al, 2012 ; Kerr et al, 2012 ; Zachariah et al, 2012 ; Liyanage et al, 2013 , 2019 ; Olson et al, 2014 ; Yasui et al, 2014 ; Sheikh et al, 2017 ; Vogel Ciernia et al, 2018 ; Martinez de Paz et al, 2019 ; Takeguchi et al, 2020 ). Information about other MECP2 transcripts and their tissue- and cell-type specific expression could be obtained through RNA sequencing or data mining of related publically available data repositories.…”

Section: Introductionmentioning

confidence: 99%

The MeCP2E1/E2-BDNF-miR132 Homeostasis Regulatory Network Is Region-Dependent in the Human Brain and Is Impaired in Rett Syndrome Patients

Pejhan

Bigio

Rastegar

2020

Front. Cell Dev. Biol.

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Rett Syndrome (RTT) is a rare and progressive neurodevelopmental disorder that is caused by de novo mutations in the X-linked Methyl CpG binding protein 2 (MECP2) gene and is subjected to X-chromosome inactivation. RTT is commonly associated with neurological regression, autistic features, motor control impairment, seizures, loss of speech and purposeful hand movements, mainly affecting females. Different animal and cellular model systems have tremendously contributed to our current knowledge about MeCP2 and RTT. However, the majority of these findings remain unexamined in the brain of RTT patients. Based on previous studies in rodent brains, the highly conserved neuronal microRNA "miR132" was suggested to be an inhibitor of MeCP2 expression. The neuronal miR132 itself is induced by Brain Derived Neurotrophic Factor (BDNF), a neurotransmitter modulator, which in turn is controlled by MeCP2. This makes the basis of the MECP2-BDNF-miR132 feedback regulatory loop in the brain. Here, we studied the components of this feedback regulatory network in humans, and its possible impairment in the brain of RTT patients. In this regard, we evaluated the transcript and protein levels of MECP2/MeCP2E1 and E2 isoforms, BDNF/BDNF, and miR132 (both 3p and 5p strands) by real time RT-PCR, Western blot, and ELISA in four different regions of the human RTT brains and their age-, post-mortem delay-, and sex-matched controls. The transcript level of the studied elements was significantly compromised in RTT patients, even though the change was not identical in different parts of the brain. Our data indicates that MeCP2E1/E2-BDNF protein levels did not follow their corresponding transcript trends. Correlational studies suggested that the MECP2E1/E2-BDNF-miR132 homeostasis regulation might not be similarly controlled in different parts of the human brain. Despite challenges in evaluating autopsy samples in rare diseases, our findings would help to shed some light on RTT pathobiology, and obscurities caused by limited studies on MeCP2 regulation in the human brain.

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“…Patients in the first group have a mutation that causes classical RTT in females, though these boys have severe neonatal encephalopathy and a lifespan of less than one year and commonly die early during childhood. The diluting effect of X chromosome aneuploidy (Klinefelter syndrome; 47 XXY)) or somatic mosaicism may be associated with a milder phenotype, similar to atypical RTT [ 28 , 29 ]. The second group presents mutations which are different from typical/classical mutations in female patients but are more compatible with life into adulthood.…”

Section: Genetic Basis Of Rett Syndrome: Link Between Genotype Andmentioning

confidence: 99%

Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease

Pejhan

Rastegar

2021

Biomolecules

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Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry de novo mutation(s) in the Methyl-CpG-Binding Protein 2 (MECP2) gene. While the majority of RTT patients have MECP2 mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1. Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA (miR132) and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the MECP2 gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and miR132.

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MeCP2_e2 partially compensates for lack of MeCP2_e1: A male case of Rett syndrome

Cited by 10 publications

References 17 publications

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

The MeCP2E1/E2-BDNF-miR132 Homeostasis Regulatory Network Is Region-Dependent in the Human Brain and Is Impaired in Rett Syndrome Patients

Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease

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