A Point Mutation in the FMR-1 Gene Associated with Fragile-X Mental Retardation

Department of Medical Genetics, University of Antwerp-UIA, Belgium.
Nature Genetics (Impact Factor: 29.35). 02/1993; 3(1):31-5. DOI: 10.1038/ng0193-31
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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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Available from: Annemieke JMH Verkerk, Aug 11, 2014
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    • "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). "
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    ABSTRACT: Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder affecting nearly 1 in 5,000 newborn males and is a leading genetic cause of autism spectrum disorder. In addition to developmental delays and intellectual impairment, FXS is characterized by seizures, attention deficit, and hypersensitivity to visual, tactile and auditory stimuli. The Fmr1 gene encodes Fragile X mental retardation protein (FMRP), which is abundant in neurons, binds select mRNAs and functions as a negative regulator of mRNA translation. A deficiency in FMRP, as in FXS and Fmr1 knockout animals, results in neuronal dysmorphology and altered synaptic function. Additionally, there is evidence for disruption of GABAergic circuits in subjects lacking FMRP. Our previous studies demonstrated widespread expression of FMRP in human auditory brainstem neurons. Given this observation, we hypothesized that FMRP is highly expressed in rat auditory brainstem neurons and that the auditory hypersensitivity characteristic of FXS results from dysfunction of brainstem networks secondary to decreased expression of FMRP. In our investigation of postnatal day 50 (P50) control rats, we found that FMRP was widely expressed in neurons of the superior olivary complex (SOC). In P50 Fmr1 knockout rats, many SOC neurons had a smaller soma when compared to controls, indicative of abnormal neuronal morphology. Additionally, neurons in the medial superior olive (MSO) were more round in Fmr1 knockout rats. There was also reduced expression of glutamic acid decarboxylase (GAD67) in neurons of the superior paraolivary nucleus (SPON) and a reduction in the number of calretinin-immunoreactive terminals associated with neurons of the medial nucleus of the trapezoid body (MNTB). Together, these findings support the conclusion that the auditory dysfunction characteristic of FXS arises, at least in part, from defective brainstem networks. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
    Neuroscience 07/2015; 303. DOI:10.1016/j.neuroscience.2015.06.061 · 3.36 Impact Factor
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    • "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. "
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    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.
    Molecular cell 04/2014; 54(3). DOI:10.1016/j.molcel.2014.03.023 · 14.02 Impact Factor
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    • "The gene comprises 17 exons spanning 38 kb of Xq27.3 (Eichler et al., 1993). Alternative splicing of the gene results in the generation of 12 protein isoforms (De Boulle et al., 1993; Brackett et al., 2013). "
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    ABSTRACT: The fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates mRNA metabolism. FMRP has been largely studied in the brain, where the absence of this protein leads to fragile X syndrome, the most frequent form of inherited intellectual disability. Since the identification of the FMRP gene in 1991, many studies have primarily focused on understanding the function/s of this protein. Hundreds of potential FMRP mRNA targets and several interacting proteins have been identified. Here, we report the identification of FMRP mRNA targets in the mammalian brain that support the key role of this protein during brain development and in regulating synaptic plasticity. We compared the genes from databases and genome-wide association studies with the brain FMRP transcriptome, and identified several FMRP mRNA targets associated with autism spectrum disorders, mood disorders and schizophrenia, showing a potential common pathway/s for these apparently different disorders.
    Frontiers in Neuroscience 10/2013; 7(7):191. DOI:10.3389/fnins.2013.00191 · 3.66 Impact Factor
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