Exclusive expression of MeCP2 in the nervous system distinguishes between brain and peripheral Rett syndrome-like phenotypes

Ross, PD; Guy, Jacky; Selfridge, Jim; Kamal, Bushra; Bahey, Noha Gamal; Tanner, K. E.; Gillingwater, Thomas H.; Jones, Ross A.; Loughrey, Christopher M.; McCarroll, Charlotte S.; Bailey, Mark E.S.; Bird, Adrian; Cobb, Stuart

doi:10.1093/hmg/ddw269

Cited by 50 publications

(64 citation statements)

References 76 publications

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“…50,51 Deletion of Mecp2 from glia in mice has relatively minor phenotypic consequences but a restoration of MeCP2 to astrocytes in an otherwise MeCP2-deficient nervous system results in a partial amelioration of phenotypes including a normalisation of breathing patterns, motor activities and anxiety. 48 As also indicated in primary culture experiments, 52 MeCP2 in glial cells may contributing to certain non-cell autonomous functions such as supporting normal dendritic morphology through the release of trophic factors within the nervous system.…”

Section: Mecp2 Is Essential For Normal Brain Functionmentioning

confidence: 99%

“…61 Overall, MeCP2 depletion studies have revealed that the majority of Rett syndrome-like behavioural, sensorimotor and autonomic phenotypes associated with are MeCP2 deficiency in the brain but that that some less extreme but clinically significant aspects of the disorder may arise independently of defects in the nervous system. 51 …”

Section: Mecp2 In Non-neural Cellsmentioning

confidence: 99%

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Clinical and biological progress over 50 years in Rett syndrome

2016

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It is fifty years since Andreas Rett first described Rett syndrome, a disorder now known to be caused by a mutation in the MECP2 gene. A compelling blend of astute clinical observations, clinical and laboratory research has already built our understanding of Rett syndrome and its biological underpinnings. We document the contributions of the early pioneers and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, the lessons from both cell and animal models and how they may inform future clinical trials. With a focus on the core criteria, we examine the relationships that have been demonstrated between genotype and clinical severity. We review what is known about the many comorbidities that occur in this disorder and how genotype may also modify their presentation. We acknowledge the important drivers that are accelerating this research program including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we conclude by highlighting the major milestones since 1966 and what they mean for the day-to-day lives of those with Rett syndrome and their families. Key pointsThere has been an explosion of knowledge about Rett syndrome in relation to its genetic basis, clinical characteristics and their relationships during the fifty years since the disorder was first described by Andreas Rett.Whilst initially the diagnosis of Rett syndrome was based only on clinical criteria, identifying its genetic cause has had a major positive impact on how clinicians diagnose the disorder but also provides new challenges as we enter the era of next generation sequencing.

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Section: Mecp2 Is Essential For Normal Brain Functionmentioning

confidence: 99%

Section: Mecp2 In Non-neural Cellsmentioning

confidence: 99%

Clinical and biological progress over 50 years in Rett syndrome

2016

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“…Wild type and MECP2 deficient mice were then compared and it was shown that the majority of neurological symptoms were absent. However bone abnormalities, fatigue, and hypo-activity was observed, which confirms brain as the primary organ for MECP2 associated phenotypes, but it also suggests that less extreme form of disorder may arise independent of the nervous system (Ross et al, 2016).…”

Section: Mecp2expression In Central Nervous System (Cns)mentioning

confidence: 68%

Role of Mecp2 Gene in Neuro Developmental Disorders

Batool¹,

Arooj²

2016

IOSR

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“…Since dendritic spines are the locations of excitatory synapses, a consequence of Mecp2 deficiency is reduced synaptic number and functional connectivity (Chao et al 2007;Chapleau et al 2009). However, MECP2's expression outside the nervous system leads to a number of systemic problems, including metabolic syndrome (Kyle et al 2016;Ross et al 2016;Kyle et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Suppressor mutations in Mecp2-null mice reveal that the DNA damage response is key to Rett syndrome pathology

Enikanolaiye

Ruston

Zeng

et al. 2019

Preprint

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Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT).We carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU), aiming to identify potential therapeutic entry points. Here we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3,177 Mecp2/Y genomes. Using exome sequencing, genetic crosses and association analysis, we identify 33 candidate genes in 30 of the suppressor lines. A network analysis shows that 61% of the candidate genes cluster into the functional categories of transcriptional repression, chromatin modification or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that are predicted to modulate synaptic signaling or lipid homeostasis. Surprisingly, mutations in genes that function in the DNA damage response (DDR) also improve symptoms in Mecp2/Y mice. The combinatorial effects of multiple loci can be resolved by employing association analysis. One line, which was previously reported to carry a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8 (Rbbp8 or CtIP), which regulates a DDR choice in double stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology directed repair and non-homologous end joining is important for neuronal cells. In this and other lines, the presence of two suppressor mutations confers better symptom improvement than one locus alone, suggesting that combination therapies could be effective in RTT.

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Exclusive expression of MeCP2 in the nervous system distinguishes between brain and peripheral Rett syndrome-like phenotypes

Cited by 50 publications

References 76 publications

Clinical and biological progress over 50 years in Rett syndrome

Clinical and biological progress over 50 years in Rett syndrome

Role of Mecp2 Gene in Neuro Developmental Disorders

Suppressor mutations in Mecp2-null mice reveal that the DNA damage response is key to Rett syndrome pathology

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