The vast majority of patients with fragile X syndrome show a folate-sensitive fragile site at Xq27.3 (FRAXA) at the cytogenetic level, and both amplification of the (CGG)n repeat and hypermethylation of the CpG island in the 5' fragile X gene (FMR-1) at the molecular level. We have studied the FMR-1 gene of a patient with the fragile X phenotype but without cytogenetic expression of FRAXA, a (CGG)n repeat of normal length and an unmethylated CpG island. We find a single point mutation in FMR-1 resulting in an lle367Asn substitution. This de novo mutation is absent in the patient's family and in 130 control X chromosomes, suggesting that the mutation causes the clinical abnormalities. Our results suggest that mutations in FMR-1 are directly responsible for fragile X syndrome, irrespective of possible secondary effects caused by FRAXA.
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"Fragile X syndrome can sometimes be misdiagnosed as only autism in the absence of the CGG-repeat expansion. However, there are two missense and other point mutations in the FMR1 gene that have been reported and described as causative of fragile X Syndrome (De Boulle et al. 1993; Lugenbeel et al. 1995; Wang et al. 1997; Collins et al. 2010; Gronskov et al. 2011; Myrick et al. 2014). Because missense mutations cannot be detected using the CGG-repeat test and because WGS data was available for every proband, loci spanning FMR1 were carefully analyzed to see if any of the probands had any possible disease-contributing mutation (e.g., p.Ile304Asn, p.Gly266Glu, IVS10 + 14C → T, and p.Ser27X). "
[Show abstract][Hide abstract] ABSTRACT: Abstract Autism spectrum disorders (ASDs) are a group of developmental disabilities that
affect social interaction and communication and are characterized by repetitive behaviors.
There is now a large body of evidence that suggests a complex role of genetics in ASDs, in
which many different loci are involved. Although many current population-scale genomic
studies have been demonstrably fruitful, these studies generally focus on analyzing a
limited part of the genome or use a limited set of bioinformatics tools. These
limitations preclude the analysis of genome-wide perturbations that may contribute to the
development and severity of ASD-related phenotypes. To overcome these limitations,
we have developed and utilized an integrative clinical and bioinformatics pipeline
for generating a more complete and reliable set of genomic variants for downstream
analyses. Our study focuses on the analysis of three simplex autism families consisting of
one affected child, unaffected parents, and one unaffected sibling. All members were
clinically evaluated and widely phenotyped. Genotyping arrays and whole-genome
sequencing were performed on each member, and the resulting sequencing data were
analyzed using a variety of available bioinformatics tools. We searched for rare variants
of putative functional impact that were found to be segregating according to de novo,
autosomal recessive, X-linked, mitochondrial, and compound heterozygote transmission
models. The resulting candidate variants included three small heterozygous copy-number
variations (CNVs), a rare heterozygous de novo nonsense mutation in MYBBP1A located
within exon 1, and a novel de novo missense variant in LAMB3. Our work demonstrates
how more comprehensive analyses that include rich clinical data and whole-genome
sequencing data can generate reliable results for use in downstream investigations.
"The number of CGG repeats ranges from 230 to over 1000 and a higher number of repeats are associated with more severe FXS phenotypes (Verkerk et al., 1991; Warren and Nelson, 1994; Till, 2010; Bagni et al., 2012). In FXS, there is reduced or silenced expression of the Fmr1 gene and therefore very little or no expression of Fragile X mental retardation protein (FMRP; Verkerk et al., 1991; De Boulle et al., 1993; Warren and Nelson, 1994; McLennan et al., 2011). Additionally, FXS is associated with a number of gross brain abnormalities such as reduced volume of the cerebellar vermis, enlargement of the 4th ventricle (Mostofsky et al., 1998; Hoeft et al., 2010) and hypertrophy of the hippocampus (Kates et al., 1997), caudate nucleus and thalamus (Reiss et al., 1995; Eliez et al., 2001; Hoeft et al., 2010). "
"Consistent with its proposed role in regulating protein synthesis, the majority of FMRP in the cell is associated with polyribosomes (Corbin et al., 1997; Darnell et al., 2011; Feng et al., 1997a, 1997b; Li et al., 2001; Mazroui et al., 2002; Stefani et al., 2004; Tamanini et al., 1996). Interestingly, a missense mutation in the KH2 domain (Ile304Asn of human FMRP) abolishes the binding of FMRP to polyribosomes and causes an aggravated form of FXS in humans (Brown et al., 1998; De Boulle et al., 1993; Feng et al., 1997a; Laggerbauer et al., 2001; Siomi et al., 1994). This suggests that RNA binding by FMRP plays a key functional role in the brain. "
[Show abstract][Hide abstract] ABSTRACT: Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and it is caused by loss of function of the fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that is involved in the translational regulation of several neuronal mRNAs. However, the precise mechanism of translational inhibition by FMRP is unknown. Here, we show that FMRP inhibits translation by binding directly to the L5 protein on the 80S ribosome. Furthermore, cryoelectron microscopic reconstruction of the 80S ribosome⋅FMRP complex shows that FMRP binds within the intersubunit space of the ribosome such that it would preclude the binding of tRNA and translation elongation factors on the ribosome. These findings suggest that FMRP inhibits translation by blocking the essential components of the translational machinery from binding to the ribosome.