Normal phenotype in two brothers with a full FMR1 mutation
Open accessAbstract
The fragile X syndrome is associated with an expanding CGG repeat in the 5' untranslated region of the first exon of the FMR1 gene. Subsequent methylation of the promoter region inhibits expression of the FMR1 gene. In two clinically normal brothers large, expanded CGG repeats and cytogenetically visible fragile sites were found. The FMR1 promoter was unmethylated and both RNA and protein could be detected. This indicates that inactivation of the FMR1 gene and not repeat expansion itself results in the fragile X phenotype. We conclude that repeat expansion does not necessarily induce methylation and that methylation is no absolute requirement for the induction of fragile sites.
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In unmethylated full mutation alleles, H3 and H4 acetylation and H3K9 methylation resemble full mutation alleles, while H3K4 and H3K27 methylation resemble normal alleles.
“acetylation of histones H3 and H4 and methylation of lysine 9 on H3 of UFM alleles are more similar to those of FM alleles, while the level of methylation of lysines 4 and 27 on H3 are more similar to that of normal alleles (18,22).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [22]
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Fragile sites, chromosomal lesions, tandem repeats, and disease
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- Authors
- Smeets, H. J. M., Smits, A. P. T., Verheij, C. E., Theelen, J. P. G., Willemsen, R., Burgt, I. V. D., Hoogeveen, A. T., Oosterwijk, J. C., & Oostra, B. A.
- Affiliations
- Radboud University Medical Center (NL)
- Erasmus University Rotterdam (NL)
- Leiden University (NL)
- Corresponding author
- Oostra, B. A.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1995-11-01
- Volume
- 4
- Issue
- 11
- Pages
- 2103-2108
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2137391937
- Cited by
- 179
- References
- 0
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 11 · 2015: 5 · 2014: 9 · 2013: 14 · 2012: 2
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- fragile X syndrome, FMR1 gene, CGG repeat expansion, promoter methylation, fragile sites, normal phenotype, gene inactivation
- MeSH terms
- Adolescent, Adult, Aged, Chromosome Mapping, Female, Fragile X Syndrome, Humans, Male, Mutation, Nerve Tissue Proteins, Pedigree, Phenotype, Gene Expression, RNA-Binding Proteins, Trinucleotide Repeats, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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