Reevaluation of FMR1 Hypermethylation Timing in Fragile X Syndrome

Frontiers in Molecular Neuroscience
Hagar Mor-Shaked, Rachel Eiges

Abstract

Fragile X syndrome (FXS) is one of the most common heritable forms of cognitive impairment. It results from a fragile X mental retardation protein (FMRP) protein deficiency caused by a CGG repeat expansion in the 5'-UTR of the X-linked FMR1 gene. Whereas in most individuals the number of CGGs is steady and ranges between 5 and 44 units, in patients it becomes extensively unstable and expands to a length exceeding 200 repeats (full mutation). Interestingly, this disease is exclusively transmitted by mothers who carry a premutation allele (55-200 CGG repeats). When the CGGs reach the FM range, they trigger the spread of abnormal DNA methylation, which coincides with a switch from active to repressive histone modifications. This results in epigenetic gene silencing of FMR1 presumably by a multi-stage, developmentally regulated process. The timing of FMR1 hypermethylation and transcription silencing is still hotly debated. There is evidence that hypermethylation varies considerably between and within the tissues of patients as well as during fetal development, thus supporting the view that FMR1 silencing is a post-zygotic event that is developmentally structured. On the other hand, it may be established in the female germ line and ...Continue Reading

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Oct 1, 2016·Genes·Hagar Mor-Shaked, Rachel Eiges

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Citations

Nov 5, 2019·Current Pharmaceutical Design·Michael Telias
Mar 31, 2018·Frontiers in Molecular Neuroscience·Regina Dahlhaus
Dec 3, 2020·International Journal of Molecular Sciences·Álvaro Fernández-Blanco, Mara Dierssen
Apr 4, 2021·American Journal of Human Genetics·Christel Depienne, Jean-Louis Mandel
May 27, 2021·Acta Neuropathologica Communications·Sanjog R ChintalaphaniKishore R Kumar

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