The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome
Open accessAbstract
A gene for Methyl-CpG binding protein 2 (MECP2), which locates Xq28, was recently found to be responsible for Rett syndrome. Although mutational analyses of MECP2 in Rett syndrome have been extensively analyzed, the mechanism(s) by which variable clinical phenotype occurred between affected monozygotic twins or sisters have not been clarified. We hypothesized that the difference of X-inactivation pattern might explain this phenomenon. With the method based on methylation-specific PCR, we analyzed polymorphic trinucleotide repeat in the human andorogen receptor gene mapped on Xq11.2-12, using DNA samples derived from previously described monozygotic twins and sisters together with their parents. Their clinical phenotypes were reported to be significantly different between siblings. We found that (1) maternally derived allele is predominantly active than paternally derived one in three out of four patients analyzed, (2) remaining one twin patient, whose ratio of active paternal allele is almost the same level as maternal allele, showed far much severe phenotype when compared with her counterpart. Together with the finding that most of the alleles with de novo mutation are from paternal X chromosome in sporadic cases, the existence of a mechanism that suppresses mutated paternal allele activation, resulting skewed X-inactivation to make clinical phenotype milder, might be speculated. Thus, when this mechanism fails to work sufficiently by an unknown reason, severer clinical phenotype could occur.
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X chromosome inactivation can be skewed so that the mutant X chromosome is more or less expressed than the wild type, resulting in a relatively more severe or milder presentation of RTT.
“XCI can be skewed preferentially so the mutant X chromosome is more or less expressed than the wild type, resulting in either a relatively more severe or milder presentation of RTT, respectively [98,99].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [98]
The Introduction and Results (section 3.2) link greater activity of the paternal X chromosome with a more severe phenotype in one of two twins. The Discussion (section 4) proposes that suppressing a mutated paternal allele might produce a milder phenotype, but treats the mutation’s paternal origin and that mechanism as possibilities, not established causes. It also reports that the sisters differed in severity without a significant difference in X-inactivation pattern. (LLM, conf=0.86)
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Research works printed but not linked: 7
- Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999; 23: 185-188.
- Cheadle JP, Gill H, Fleming N, Maynard J, Kerr A, Leonard H, Krawczak M, Cooper DN, Lynch S, Thomas N, Hughes H, Hulten M, Ravine D, Sampson JR, Clarke A. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: Correlation of disease severity with mutation type and location. Hum Mol Genet 2000; 9: 1119-1129.
- Ogawa A, Mitsudome A, Yasumoto S, Matsumoto T. Japanese monozygotic twins with Rett syndrome. Brain Dev 1997; 19: 568-570.
- Miyamoto A, Yamamoto M, Takahashi S, Oki J. Classical Rett syndrome in sisters: variability of clinical expression. Brain Dev 1997; 19: 492-494.
- Amir RE, Van den Veyver IB, Schultz R, Malicki DM, Tran CQ, Dahle EJ, Philippi A, Timar L, Percy AK, Motil KJ, Lichtarge O, Smith EO, Glaze DG, Zoghbi HY. Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann Neurol 2000; 47, 670-679.
- Kubota T, Nonoyama S, Tonoki H, Masuno M, Imaizumi K, Kojima M, Wakui K, Shimadzu M, Fukushima Y. A new assay for the analysis of X-chromosome inactivation based on methylation-specific PCR. Hum Genet 1999; 104: 49-55.
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Rett syndrome: a neurological disorder with metabolic components
Kyle, S. M., Vashi, N., & Justice, M. J. (2018) · Open Biology · doi:10.1098/rsob.170216 · Cited by 213 · see citing works
- Authors
- Ishii, T., Makita, Y., Ogawa, A., Amamiya, S., Yamamoto, M., Miyamoto, A., & Oki, J.
- Affiliations
- Asahikawa Medical College Hospital (JP)
- Fukuoka University (JP)
- Corresponding author
- Ishii, Takuma
- Venue
- Brain and Development
- Publisher
- Elsevier BV
- Published
- 2001-12
- Volume
- 23
- Issue
- Suppl 1
- Pages
- S161-S164
- ISSN
- 0387-7604 (ISSN-L)
- OpenAlex
- W1986352415
- Cited by
- 61
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 4 · 2013: 4 · 2012: 4
- FWCI
- 1.46
- Type
- journal article
- Language
- en
- Open access
- Locations
- Brain and Development (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Asahikawa Medical University Collection and Research (Asahikawa Medical University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- Rett syndrome, MeCP2, X chromosome inactivation, variable expressivity, monozygotic twins, androgen receptor, trinucleotide repeat polymorphism, allele-specific expression, paternal allele, de novo mutations, Xq28, methylation-specific PCR
- MeSH terms
- Adult, Amino Acid Sequence, Base Sequence, Chromosomal Proteins, Non-Histone, DNA Mutational Analysis, DNA-Binding Proteins, Dosage Compensation, Genetic, Female, Humans, Male, Mutation, Pedigree, Phenotype, Repressor Proteins, Twins, Monozygotic, Rett Syndrome, Point Mutation, Disease Progression, Allelic Imbalance, Methyl-CpG-Binding Protein 2
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