DNA methylation represses FMR-1 transcription in fragile X syndrome
Abstract
Fragile X syndrome is the most frequent form of inherited mental retardation and segregates as an X-linked dominant with reduced penetrance. Recently, we have identified the FMR-1 gene at the fragile X locus. Two molecular differences of the FMR-1 gene have been found in fragile X patients: a size increase of an FMR-1 exon containing a CGG repeat and abnormal methylation of a CpG island 250 bp proximal to this repeat. Penetrant fragile X males who exhibit these changes typically show repression of FMR-1 transcription and the presumptive absence of FMR-1 protein is believed to contribute to the fragile X phenotype. It is unclear, however, if either or both molecular differences in FMR-1 gene is responsible for transcriptional silencing. We report here the prenatal diagnosis of a male fetus with fragile X syndrome by utilizing these molecular differences and show that while the expanded CGG-repeat mutation is observed in both the chorionic villi and fetus, the methylation of the CpG island is limited to the fetal DNA (as assessed by BssHII digestion). We further demonstrate that FMR-1 gene expression is repressed in the fetal tissue, as is characteristic of penetrant males, while the undermethylated chorionic villi expressed FMR-1. Since the genetic background of the tissues studied is identical, including the fragile X chromosome, these data indicate that the abnormal methylation of the FMR-1 CpG-island is responsible for the absence of FMR-1 transcription and suggests that the methylation may be acquired early in embryogenesis.
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Over 200 CGG repeats in FMR1 lead to embryonic methylation of the promoter, subsequent silencing of the gene, and lack of FMRP.
“Repeats less than 55 are in the benign range, whereas over 200 repeats lead to embryonic methylation of the promoter, subsequent silencing of the gene, and therefore lack of the FMR1 protein (FMRP, Sutcliffe et al., 1992).”
From Astrocytes in fragile X syndrome (2024) · cites this paper as Sutcliffe et al., 1992
Methylation inhibits FMR1 transcription, leading to absence of the FMRP protein product.
“As a consequence, gene transcription is inhibited, leading to the absence of its protein product FMRP (17).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [17]
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- Authors
- Sutcliffe, J. S., Nelson, D. L., Zhang, F., Pieretti, M., Caskey, C. T., Saxe, D., & Warren, S. T.
- Affiliations
- Howard Hughes Medical Institute (US)
- Institute of Molecular Genetics (RU)
- Emory University (US)
- Corresponding author
- Warren, Stephen T.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1992
- Volume
- 1
- Issue
- 6
- Pages
- 397-400
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2096252283
- Cited by
- 680
- References
- 0
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 13 · 2023: 11 · 2022: 20 · 2021: 23 · 2020: 15 · 2019: 22 · 2018: 16 · 2017: 21 · 2016: 24 · 2015: 29 · 2014: 35 · 2013: 32 · 2012: 24
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Human Genome Research Institute (HG00038)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 20521)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- fragile X syndrome, DNA methylation, CpG islands, CGG repeat expansion, transcriptional repression, prenatal diagnosis, chorionic villi, FMRP, X-linked dominant inheritance, penetrance
- MeSH terms
- Base Sequence, DNA, Exons, Female, Fetus, Fragile X Syndrome, Humans, Male, Methylation, Nerve Tissue Proteins, Pedigree, Pregnancy, Repetitive Sequences, Nucleic Acid, Transcription, Genetic, Restriction Mapping, Chorionic Villi Sampling, Polymerase Chain Reaction, RNA-Binding Proteins, Fragile X Messenger Ribonucleoprotein 1
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