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 ofvarious neurodevelopmental, cognitive, 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 associatedwith the premutation alleles. The first one is the late onsetneurodegenerative disorder termed fragile X-associated 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 withthenormal rangei.e.,41-54CGGs), tothepsychologicalandclinical manifestations, already associated with premutation alleles, are discussed. Special emphasis has been placed on the possibility that the modest elevation of 'toxic' FMR1 mRNA in the carriers of grey zone alleles may present an additional risk for some neurodegenerative diseases, such as those associated with parkinsonism, by synergizing with either other susceptibility genes or environmental poisons. The present status ofthe treatment of fragile X-related disorders, especially FXS, is presented in the last section of this chapter. Pharmacological interventions in this syndrome have recently extended beyond stimulants and antipsychotic medications, and the latest trials involving a group of GluR5 antagonists aim to ascertain if these substances have the potential to reverse some of the neurobiological abnormalities of FXS.

Figure 1

Standardized percent deviation of FSIQ-adjusted summary and subtest (Wechsler) scores from the normal mean due to the effect of premutation (upper figure), and full mutation (lower figure) separately for males and females, based on pedigree models. The baseline represents the FSIQ of a 100. Reproduced from Loesch DZ et al. Am J Med Genet A 2003; 122A(1):13-23.

Figure 2

Axial FLAIR images of the brain of the 64 year old male carrier of 80 CGG repeats with typical manifestations of FXTAS comprising marked cerebellar ataxia, intention tremor, autonomic failure (originally diagnosed with multiple system atrophy, MSA). Marked bilateral T2 hyperintense signals within the middle cerebellar peduncles (MCP sign), combined with symmetrical T2 hyperintense signals within the corona radiate and considerable cerebral and cerebellar atrophy are evident from the images. Reproduced from Loesch DZ et al. Clinical Genetics 2005; 67(5):412-417.

Figure 3

Eosinophilic inclusions in the nucleus of both neurons (left panel) and astrocytes (right panel) from a patient with FXTAS. Picture courtesy of Claudia Greco MD and Paul Hagerman MD, PhD.

Figure 4

Nonparametric local fit (Locfit) and piecewise regression fit to the log-transformed mRNA levels versus CGG repeat numbers for data from all three allelic categories: Normal, GZ and PM. Reproduced from Loesch DZ et al. J Med Genet 2007; 44(3):198-204.