Methyl-CpG-binding protein 2 ( MECP2 ) mutation type is associated with disease severity in Rett syndrome
Open accessAbstract
BACKGROUND: Rett syndrome (RTT), a neurodevelopmental disorder that primarily affects girls, is characterised by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress. More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. Surprisingly, although the disorder is caused by mutations in a single gene, disease severity in affected individuals can be quite variable. To explore the source of this phenotypic variability, we propose that specific MECP2 mutations lead to different degrees of disease severity. METHODS: Using a database of 1052 participants assessed over 4940 unique visits, the largest cohort of both typical and atypical RTT patients studied to date, we examined the relationship between MECP2 mutation status and various phenotypic measures over time. RESULTS: In general agreement with previous studies, we found that particular mutations, such as p.Arg133Cys, p.Arg294X, p.Arg306Cys, 3° truncations and other point mutations, were relatively less severe in both typical and atypical RTT. In contrast, p.Arg106Trp, p.Arg168X, p.Arg255X, p.Arg270X, splice sites, deletions, insertions and deletions were significantly more severe. We also demonstrated that, for most mutation types, clinical severity increases with age. Furthermore, of the clinical features of RTT, ambulation, hand use and age at onset of stereotypies are strongly linked to overall disease severity. CONCLUSIONS: We have confirmed that MECP2 mutation type is a strong predictor of disease severity. These data also indicate that clinical severity continues to become progressively worse regardless of initial severity. These findings will allow clinicians and families to anticipate and prepare better for the needs of individuals with RTT.
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MECP2 mutation status is a strong predictor of disease severity.
“Therefore, MECP2 mutation status is a strong predictor of disease severity, but phenotype variation commonly occurs between individuals with the same MECP2 mutation and is attributed to differences in X chromosome inactivation (XCI) [97].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [96]
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MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription
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Specific mutations in <i>Methyl-CpG-Binding Protein 2</i> confer different severity in Rett syndrome
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- Authors
- Cuddapah, V. A., Pillai, R. B., Shekar, K. V., Lane, J. B., Motil, K. J., Skinner, S. A., Tarquinio, D. C., Glaze, D. G., McGwin, G., Kaufmann, W. E., Percy, A. K., Neul, J. L., & Olsen, M. L.
- Affiliations
- University of Alabama at Birmingham (US)
- Civitan International (US)
- Baylor College of Medicine (US)
- Greenwood Genetic Center (US)
- Boston Children's Hospital (US)
- Corresponding author
- Olsen, Michelle L
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2014-01-07
- Volume
- 51
- Issue
- 3
- Pages
- 152-158
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- PMC
- PMC4403764
- OpenAlex
- W2099517884
- Cited by
- 311
- References
- 4
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 35 · 2023: 23 · 2022: 24 · 2021: 30 · 2020: 30 · 2019: 26 · 2018: 25 · 2017: 17 · 2016: 24 · 2015: 26 · 2014: 9
- FWCI
- 16.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Civitan International
- National Institutes of Health (HD061222, HD38985)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-38985, HD-061222, P30HD038985, U54HD061222)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- Rett syndrome, MECP2 mutations, disease severity, phenotypic variability, mutation types, truncating mutations, splice site mutation, nonsense mutation, frameshift deletion, insertion, age-related disease progression, ambulation, hand use, stereotypy, atypical Rett syndrome
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Mutation, Severity of Illness Index, Rett Syndrome, Methyl-CpG-Binding Protein 2, Young Adult, Genetic Association Studies
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