Unstable Mutations in the FMR1 Gene and the Phenotypes

Abstract

Fragile X syndrome (FXS), a severe neurodevelopmental anomaly, and one of the earliest disorders linked to an unstable ('dynamic') mutation, is caused by the large (>200) CGG repeat expansions in the noncoding portion of the FMR1 (Fragile X Mental Retardation-1) gene. These expansions, termed full mutations, normally silence this gene's promoter through methylation, leading to a gross deficit of the Fragile X Mental Retardation Protein (FMRP) that is essential for normal brain development. Rare individuals with the expansion but with an unmethylated promoter (and thus, FMRP production), present a much less severe form of FXS.However, a unique feature of the relationship between the different sizes of CGG expanded tract and phenotypic changes is that smaller expansions (<200) generate a series of different clinical manifestations and/or neuropsychological changes. The major part of this chapter is devoted to those FMR1 alleles with small (55-200) CGG expansions, termed 'premutations', which have the potential for generating the full mutation alleles on mother-offspring transmission, on the one hand, and are associated with some phenotypic changes, on the other. Thus, the role of several factors known to determine the rate of CGG expansion in the premutation alleles is discussed first. Then, an account of various neurodevelopmental, congnitive, behavioural and physical changes reported in carriers of these small expansions is given, and possible association of these conditions with a toxicity of the elevated FMR1 gene's transcript (mRNA) is discussed.The next two sections are devoted to major and well defined clinical conditions associated with the premutation alleles. The first one is the late onset neurodegenerative disorder termed fragile Xassociated tremor ataxia syndrome (FXTAS). The wide range of clinical and neuropsychological manifestations of this syndrome, and their relevance to elevated levels of the FMR1 mRNA, are described. Another distinct disorder linked to the CGG repeat expansions within the premutation range is fragile X-associated primary ovarian insufficiency (FXPOI) in females, and an account of the spectrum of manifestations of this disorder, together with the latest findings suggesting an early onset of the ovarian changes, is given.In the following section, the most recent findings concerning the possible contribution of FMR1 'grey zone' alleles (those with the smallest repeat expansions overlapping with the normal range

Validation of a Commercially Available Screening Tool for the Rapid Identification of CGG Trinucleotide Repeat Expansions in FMR1

“…11 Accumulated evidence later found that PM carriers may develop fragile X-associated conditions such as fragile Xeassociated tremor/ataxia syndrome 9 and fragile Xeassociated primary ovarian insufficiency, a condition defined as menopause before 40 years of age. 15 Female PM carriers have an estimated 20% risk of fragile Xeassociated primary ovarian insufficiency, 12 whereas approximately 8% of female PM carriers and 40% of male PM carriers develop fragile Xeassociated tremor/ataxia syndrome. 16 Some studies now suggest that PM carriers may have various degrees of learning disabilities and anxiety disorders.…”

Caries experience and salivary aspects in individuals with fragile X syndrome

“…1,2,3 This syndrome is related to a mutation on the X chromosome, in the Fragile X Mental Retardation 1 gene (FMR-1), which can be identified microscopically by a constriction called a 'fragile site' on the long arm of chromosome X and is associated with mechanisms of genetic inheritance that are not usually correlated with phenotypic abnormalities. 4,5 Unlike Down syndrome, which does not tend to repeat itself in families, FXS has a high risk of familial occurrence in brothers. It is a dominant inheritance disorder linked to chromosome X.…”

Impact of <b><i>FMR1</i></b> Pre-Mutation Status on Blastocyst Development in Patients Undergoing Pre-Implantation Genetic Diagnosis

“…The pathologic phenotypes associated with FMR1 occur due to the expansion of its CGG trinucleotide repeats [1,2] . For example, most FMR1 -related neuropsychiatric disorders are caused by large CGG repeats (>200), that is, full mutations of the FMR1 gene [3][4][5] . Carriers of the FMR1 pre-mutation with 55-200 CGG repeats are known to have diminished ovarian reserve and are at risk for pre-…”