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 transmitted to the fetus as an integral part of the mutation. This short review summarizes the data collected to date concerning the timing of FMR1 epigenetic gene silencing and reassess the evidence in favor of the theory that gene inactivation takes place by a developmentally regulated process around the 10th week of gestation.
Highlights
Reviewed by: Enzo Lalli, INSERM, France Eleonora Napoli, University of California, Davis, United States Oskar A
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
Fragile X syndrome (FXS; OMIM#300624) is one of the most common heritable forms of cognitive impairment (1 in 4000 male and 1 in 8000 female births), and is the leading known genetic cause of autism. It is inherited as an X-linked condition and results from a deficiency in the fragile X mental retardation protein (FMRP; McLennan et al, 2011)
Summary
Reviewed by: Enzo Lalli, INSERM, France Eleonora Napoli, University of California, Davis, United States Oskar A. The idea that FMR1 is inactivated fairly late during embryogenesis is not well supported by the high rate of methylation mosaicism observed in FXS human embryonic stem cell lines (hESCs; Avitzour et al, 2014).
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