Mild overexpression of MeCP2 causes a progressive neurological disorder in mice

Collins, Andrew; Levenson, Jonathan M.; Vilaythong, Alexander P.; Richman, Ronald; Armstrong, Dawna L.; Noebels, Jeffrey L.; Sweatt, J. David; Zoghbi, Huda Y.

doi:10.1093/hmg/ddh282

Cited by 550 publications

(638 citation statements)

References 54 publications

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“…12 designed to include BAC clones for MECP2, based on the observation that increased MECP2 levels cause progressive neurologic features in a mouse model. 33,34 CMA detection of MECP2 duplications was demonstrated on our initial patients 1 and 2, along with their asymptomatic mothers, using our version 4 microarray (366 FISH-verified BAC clones). 27 Figure 2A shows representative CMA data from patient 1, which was cohybridized with a normal male genome; the results show a twofold increased copy number of the two Xq28 genomic clones on the CMA version 4 microarray (i.e., BAC RP11-119A22 including MECP2, and RP11-24410 including the flanking L1CAM gene).…”

Section: Mecp2 Gene Duplications In Male Patientsmentioning

confidence: 84%

“…These patient findings are consistent with data from transgenic mouse models overexpressing the wild-type human MECP2 protein. 33,34 These mice appear clinically normal at birth but develop Rett-like progressive neurologic problems including motor dysfunction, hypoactivity, tremors, and ataxia, and die prematurely. 33 Higher MECP2 protein levels were found to correlate with more severe phenotypes in these mice.…”

Section: Discussionmentioning

confidence: 99%

“…33,34 These mice appear clinically normal at birth but develop Rett-like progressive neurologic problems including motor dysfunction, hypoactivity, tremors, and ataxia, and die prematurely. 33 Higher MECP2 protein levels were found to correlate with more severe phenotypes in these mice. 33 Duplications within the human genome are increasingly recognized as a cause of neurodegenerative phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

Gaudio

Fang

Scaglia

et al. 2006

Genetics in Medicine

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Purpose: Mutations in the MECP2 gene are associated with Rett syndrome, an X-linked mental retardation disorder in females. Mutations also cause variable neurodevelopmental phenotypes in rare affected males. Recent clinical testing for MECP2 gene rearrangements revealed that entire MECP2 gene duplication occurs in some males manifesting a progressive neurodevelopmental syndrome. Methods: Clinical testing through quantitative DNA methods and chromosomal microarray analysis in our laboratories identified seven male patients with increased MECP2 gene copy number.Results: Duplication of the entire MECP2 gene was found in six patients, and MECP2 triplication was found in one patient with the most severe phenotype. The Xq28 duplications observed in these males are unique and vary in size from approximately 200 kb to 2.2 Mb. Three of the mothers who were tested were asymptomatic duplication carriers with skewed X-inactivation. In silico analysis of the Xq28 flanking region showed numerous low-copy repeats with potential roles in recombination. Conclusions: These collective data suggest that increased MECP2 gene copy number is mainly responsible for the neurodevelopmental phenotypes in these males. These findings underscore the allelic and phenotypic heterogeneity associated with the MECP2 gene and highlight the value of molecular analysis for patient diagnosis, family members at risk, and genetic counseling. Genet Med 2006:8(12):784-792.

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Section: Mecp2 Gene Duplications In Male Patientsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

Gaudio

Fang

Scaglia

et al. 2006

Genetics in Medicine

Self Cite

250

264

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“…In addition, changes in DNA methylation can affect levels of histone acetylation (Becker et al, 1987;Collins et al, 2004;Cross et al, 1997;Jones et al, 1998;Nan et al, 1997Nan et al, , 1998 and we have demonstrated in vitro that DNMT inhibition significantly attenuates PKC-induced H3 acetylation (Levenson et al, 2006). Therefore, we hypothesized that the blockade of memory consolidation by 5-AZA could be partially due to modulation of histone acetylation.…”

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confidence: 98%

DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity

Miller

Campbell

Sweatt

2008

Neurobiology of Learning and Memory

384

359

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A clear understanding is developing concerning the importance of epigenetic-related molecular mechanisms in transcription-dependent long-term memory formation. Chromatin modification, in particular histone acetylation, is associated with transcriptional activation, and acetylation of histone 3 (H3) occurs in Area CA1 of the hippocampus following contextual fear conditioning training. Conversely, DNA methylation is associated with transcriptional repression, but is also dynamically regulated in Area CA1 following training. We recently reported that inhibition of the enzyme responsible for DNA methylation, DNA methyltransferase (DNMT), in the adult rat hippocampus blocks behavioral memory formation. Here we report that DNMT inhibition also blocks the concomitant memory-associated H3 acetylation, without affecting phosphorylation of its upstream regulator, extracellular signal-regulated kinase (ERK). Interestingly, the DNMT inhibitor-induced deficit in memory consolidation, along with deficits in long-term potentiation, can be rescued by pharmacologically increasing levels of histone acetylation prior to DNMT inhibition. These observations suggest that DNMT activity is not only necessary for memory and plasticity, but that DNA methylation may work in concert with histone modifications to regulate plasticity and memory formation in the adult rat hippocampus.

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“…One NID mutation, R306C, causes a severe RTT-like phenotype in mice (13,15,16). Moreover, mouse models of MeCP2 duplication syndrome suggest that both the MBD and the NID must be intact for this adverse molecular pathology to develop (16,17).…”

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confidence: 99%

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Kruusvee

Lyst

Taylor

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. The majority of RTT missense mutations disrupt the interaction of the MeCP2 with DNA or the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid receptors (SMRT) corepressor complex. Here, we show that the "NCoR/SMRT interaction domain" (NID) of MeCP2 directly contacts transducin beta-like 1 (TBL1) and TBL1 related (TBLR1), two paralogs that are core components of NCoR/SMRT. We determine the cocrystal structure of the MeCP2 NID in complex with the WD40 domain of TBLR1 and confirm by in vitro and ex vivo assays that mutation of interacting residues of TBLR1 and TBL1 disrupts binding to MeCP2. Strikingly, the four MeCP2-NID residues mutated in RTT are those residues that make the most extensive contacts with TBLR1. Moreover, missense mutations in the gene for TBLR1 that are associated with intellectual disability also prevent MeCP2 binding. Our study therefore reveals the molecular basis of an interaction that is crucial for optimal brain function.T he methyl-CpG-binding protein 2 (MeCP2) is a chromatinassociated factor that is highly expressed in the brain (1, 2). Loss-of-function mutations in MeCP2 lead to the severe pediatric neurological disorder, Rett syndrome (RTT) (3), which affects around one in 10,000 girls. In addition, extra copies of the gene cause MeCP2 duplication syndrome (4, 5), a distinct intellectual disability disorder that predominantly affects males (6). The importance of MeCP2 for brain function has prompted investigation of its molecular function. The protein was identified because of its ability to bind DNA via its methyl-CpG-binding domain (MBD) (1, 7) and many residues mutated in RTT disrupt this interaction (8-11). In addition to DNA, numerous protein partners of MeCP2 have been reported (11). Of these protein partners, only the interactions with the nuclear receptor corepressor (NCoR) and its close relative silencing mediator of retinoic acid and thyroid receptors (SMRT) (12-14) are known to be disrupted by RTT missense mutations (13). Accordingly, Rett missense mutations outside the MBD are found clustered within the so-called "NCoR/SMRT interaction domain" (NID) (13) (Fig. 1A and Fig. S1A). One NID mutation, R306C, causes a severe RTT-like phenotype in mice (13,15,16). Moreover, mouse models of MeCP2 duplication syndrome suggest that both the MBD and the NID must be intact for this adverse molecular pathology to develop (16,17).These findings indicate that the NID mediates an essential function of MeCP2. This function may be recruitment of the NCoR/ SMRT corepressor complexes to chromatin. Alternatively, the NID may perform other essential roles, such as DNA binding, whose loss leads to RTT (16). In an attempt to distinguish among these possibilities, we investigated the molecular basis of the interaction between MeCP2 and NCoR/SMRT. The latter are ∼1.2-MDa multisubunit complexes that include NCoR1 (and/or SMRT), HDAC3, GPS2, and...

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Mild overexpression of MeCP2 causes a progressive neurological disorder in mice

Cited by 550 publications

References 54 publications

Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

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