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Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation
Open accessAbstract
Rett syndrome (RTT) is a neurodevelopmental autism spectrum disorder that affects girls due primarily to mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). The majority of RTT patients carry missense and nonsense mutations leading to a hypomorphic MECP2, while null mutations leading to the complete absence of a functional protein are rare. MECP2 is an X-linked gene subject to random X-chromosome inactivation resulting in mosaic expression of mutant MECP2. The lack of human brain tissue motivates the need for alternative human cellular models to study RTT. Here we report the characterization of a MECP2 mutation in a classic female RTT patient involving rearrangements that remove exons 3 and 4 creating a functionally null mutation. To generate human neuron models of RTT, we isolated human induced pluripotent stem (hiPS) cells from RTT patient fibroblasts. RTT-hiPS cells retained the MECP2 mutation, are pluripotent and fully reprogrammed, and retained an inactive X-chromosome in a nonrandom pattern. Taking advantage of the latter characteristic, we obtained a pair of isogenic wild-type and mutant MECP2 expressing RTT-hiPS cell lines that retained this MECP2 expression pattern upon differentiation into neurons. Phenotypic analysis of mutant RTT-hiPS cell-derived neurons demonstrated a reduction in soma size compared with the isogenic control RTT-hiPS cell-derived neurons from the same RTT patient. Analysis of isogenic control and mutant hiPS cell-derived neurons represents a promising source for understanding the pathogenesis of RTT and the role of MECP2 in human neurons.
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“As a proof-of-principle, several recent studies have now shown that hiPSC-derived neurons from patients with psychiatric disorders exhibit significant aberrations in neuronal connectivity, synapse maturation, and synaptic function compared with those of healthy controls (Brennand et al., 2011; Cheung et al., 2011; Marchetto et al., 2010; Pasca et al., 2011).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Cheung et al., 2011
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Metadata
- Authors
- Cheung, A. Y. L., Horvath, L. M., Grafodatskaya, D., Pasceri, P., Weksberg, R., Hotta, A., Carrel, L., & Ellis, J.
- Affiliations
- University of Toronto (CA)
- Pennsylvania State University (US)
- Hospital for Sick Children (CA)
- Biologie du Développement et Cellules Souches (FR)
- Corresponding author
- Ellis, James
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-03-03
- Volume
- 20
- Issue
- 11
- Pages
- 2103-2115
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3090191
- OpenAlex
- W2103756619
- Cited by
- 271
- References
- 61
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 13 · 2023: 15 · 2022: 5 · 2021: 3 · 2020: 21 · 2019: 15 · 2018: 19 · 2017: 19 · 2016: 20 · 2015: 30 · 2014: 19 · 2013: 24 · 2012: 42
- FWCI
- 20.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Human Molecular Genetics (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (RMF92090, 94505_1, MOP102649)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD056452, R01HD056452)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Keywords
- Rett syndrome, MeCP2, X chromosome inactivation, induced pluripotent stem cells, isogenic cell lines, fibroblast reprogramming, neurodevelopmental disorders, autism spectrum disorder
- MeSH terms
- Brain, Cell Differentiation, Cell Line, Chromosome Mapping, Exons, Female, Gene Expression Regulation, Genotype, Humans, Immunohistochemistry, Karyotyping, Male, Mutation, Neurons, Phenotype, Rett Syndrome, DNA Fingerprinting, Chromosomes, Human, X, X Chromosome Inactivation, Genes, X-Linked, Methyl-CpG-Binding Protein 2, Induced Pluripotent Stem Cells
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