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Rett Syndrome Plasmid Collection and Resource Center



The (Link opens in a new window)Rett Syndrome Research Trust (RSRT) was launched in 2008 to drive the development of treatments and cures for Rett Syndrome and related MECP2 disorders. The RSRT has a comprehensive, strategic and aggressive plan to use gene editing, MECP2 reactivation, RNA editing, gene replacement therapy, RNA trans-splicing, and protein replacement to reverse the impacts of this disease. Addgene is working with the RSRT along with individual laboratories to assemble a Rett Syndrome plasmid resource for the scientific research community.

Background

Rett Syndrome

Rett syndrome is a neurodevelopmental disorder that presents in early toddlerhood primarily affecting females at an incidence of approximately 1:10,000. It is characterized by apparently normal development through the first 6 months of age, followed by developmental delay between 6 and 18 months of age. A defining feature, with onset typically between 18 to 30 months, is regression of previously acquired skills, notably loss of acquired purposeful hand movements and regression of speech. In contrast to the sustained loss of skills in neurodegenerative conditions, the regressive period in Rett syndrome is self-limited, after which a period of developmental stabilization or even limited recovery of skills occurs.

Diagnosis of Rett syndrome is currently based on specific clinical diagnostic criteria, defined as the presence of relatively normal early development, regression with a loss of spoken language and hand skills, development of repetitive hand stereotypies, and gait dysfunction or absence of gait. Greater than 95% of individuals who meet diagnostic criteria have disease-causing mutations in the gene methyl-CpG binding protein 2 (MECP2).

MECP2

Rett syndrome is an X-linked disorder caused from loss-of-function mutations in the MECP2 gene. Causative mutations for Rett syndrome typically arise spontaneously, although in rare cases Rett syndrome can be inherited. In females, random X inactivation results in approximately half of cells expressing wild-type MECP2 and half expressing mutant MECP2. Skewing of these X inactivation ratios can affect disease severity.

The MECP2 protein is a global transcriptional regulator of thousands of genes and studies have suggested roles in transcriptional repression, activity dependent de-repression, chromatin remodeling, gene activation, and more. How loss of MECP2 protein function results in Rett syndrome is not clear, however, the ability to bind to methylated DNA and recruit known co-repressors or other transcriptional modifiers suggests the major function of MECP2 is to regulate gene expression either locally or globally.

The MECP2 protein contains several functional domains, including:

  • the N-terminal Domain (NTD)
  • the Methyl Binding Domain (MBD)
  • a Transcriptional Repressor Domain (TRD)
    • the TRD contains a Nuclear receptor Co-Repressor 1/Silencing Mediator of Retinoic acid and Thyroid hormone receptor (NCoR/SMRT) interacting domain (NID)
    • a nuclear localization signal (not essential for localization)
  • the C-terminal Domain (CTD)

The most common missense mutations cluster in the MBD and NID demonstrating the importance of binding to methylated DNA and the recruitment of the NCoR complex for proper nervous system function.

While there is wide variability in symptoms even within patients with the same mutation, the location and type of MECP2 mutation can be a strong predictor of symptom severity. Broadly, early gene disruptions, missense mutations located in the MBD, and truncations prior to the NID are more severe than mutations further downstream in the NID and C-terminus. A large number of mutations are known to cause Rett syndrome, however, eight recurrent missense and nonsense mutations (R106W, R133C, T158M, R168X, R255X, R270X, R294X, and R306C) account for almost 46% of all Rett syndrome cases.

Research Milestones

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Animal Models

Studies of the MECP2 protein in mouse and rat models have accelerated our understanding of Rett syndrome at the molecular level. They are also an important tool for developing therapeutic strategies to treat Rett syndrome and restore functional MECP2 in cells.

The following cell lines are available directly from the labs in which they were created. Find their contact information by following the link to their laboratory website.

Mouse Line Mutation (DNA) Background Strain Purpose Publication PI
Mecp2 NLucTom Knock-in of NLuc-tdTomato at endogenous MECP2 locus Castaneus MECP2-NLuc-tdTomato mouse reporter cell line (Link opens in a new window) PMID: 35148843 Joost Gribnau
Xist 2lox/2lox Conditional Xist, Lox sites flanking exon 1,2,3 C57BL/6 Mouse line with conditional deletion of Xist Unpublished Joost Gribnau

Human Cell Line Models

Induced pluripotent stem cells (iPSCs) are a powerful system for generating Rett syndrome-specific differentiated cells that can be used to understand the mechanisms of the disease and for the development of successful therapeutics.

The following cell lines are available directly from the labs in which they were created. Find their contact information by following the link to their laboratory website.

Cell Line Mutation (DNA) Mutation (protein) Sex Source of Material Publication PI
N126I A377T N126I M Fibroblasts & iPSC (Link opens in a new window) PMID: 26944080 (Link opens in a new window)Alysson Muotri
Q83X C247T Q83X M Fibroblasts & iPSC (Link opens in a new window) PMID: 26944080 (Link opens in a new window)Alysson Muotri
c.806delG 806delG G269Afs*20 M Fibroblasts & iPSC Unpublished (Link opens in a new window)Wendy Gold
A140V C419T A140V M Fibroblasts Unpublished (Link opens in a new window)Wendy Gold
AN_BU 808delC Arg270Glufs*19 F Fibroblasts & iPSC Unpublished (Link opens in a new window)Wendy Gold
BO_DI 806delG G269Afs*20 F Fibroblasts Unpublished (Link opens in a new window)Wendy Gold
HO_AN G917A R306H F Fibroblasts Unpublished (Link opens in a new window)Wendy Gold

For more information on generating iPSCs using plasmids, please see Addgene's Plasmids for Stem Cell Research page.

CRISPR Tools

CRISPR technology is a promising therapeutic approach for precise editing of mutations in the MECP2 gene. Please refer to Addgene's CRISPR Guide for a general introduction to CRISPR technology or the mammalian CRISPR resources for a full selection of plasmids expressing Cas9 and empty gRNA backbones. A few examples of additional CRISPR resources can be found below:

Plasmids

MECP2 Plasmids

The table below highlights plasmids that express or target the MECP2 gene. Use the search bar or sort buttons to find plasmids based on:

  • Expression system (mammalian or bacterial)
  • Insert species (mouse or human)
  • Mutation
ID Plasmid Description Gene/Insert Mutations PI

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External Resources

Research Databases

Mouse and Cell Line Repositories

Tissue Banks

Antibodies

Additional Resources

Funding Opportunities

References

Amir et al. 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 23, 185–188. (Link opens in a new window) PMID: 10508514

Archer et al. 2007. Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation. J Med Genet. 44, 148–152. (Link opens in a new window) PMID: 16905679

Cuddapah et al. 2014. Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J Med Genet. 51, 152–158. (Link opens in a new window) PMID: 24399845

Guy et al. 2007. Reversal of Neurological Defects in a Mouse Model of Rett Syndrome. Science. 315, 1143–1147.(Link opens in a new window) PMID: 17289941

Hagberg et al. 1983. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol. 14, 471–479. (Link opens in a new window) PMID: 6638958

Kankirawatana et al. 2006. Early progressive encephalopathy in boys and MECP2 mutations. Neurology. 67, 164–166. (Link opens in a new window) PMID: 16832102

Krishnaraj et al. 2017. RettBASE: Rett syndrome database update. Hum Mutat. 38, 922–931.(Link opens in a new window) PMID: 28544139

Laurvick et al. 2006. Rett syndrome in Australia: a review of the epidemiology. J Pediatric. 148(3):347-352. (Link opens in a new window) PMID: 16615965

Leonard et al. 2017. Clinical and biological progress over 50 years in Rett syndrome. Nat Rev Neurol. 13, 37–51. PMID: 27934853

Neul et al. 2008. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 70, 1313–1321. PMID: 18337588

Neul et al. 2010. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 68, 944–950. PMID: 21154482

Neul et al. 2019. The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2. Am J Med Genet B Neuropsychiatr Genet. 180, 55–67. PMID: 30536762

Shahbazian et al. 2002. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet. 11, 115–124. PMID: 11809720

Tarquinio et al. 2015. Age of diagnosis in Rett syndrome: patterns of recognition among diagnosticians and risk factors for late diagnosis. Pediatr Neurol. 52, 585-591.e2. PMID: 25801175

Tillotson and Bird. 2019. The Molecular Basis of MeCP2 Function in the Brain. J Mol Biol. 17;S0022-2836(19)30595-9. PMID: 31629770

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