Trends in Genetics
Of mice and the fragile X syndrome
Section snippets
Behavioral changes in the fragile X knockout mouse
Interrupting the murine Fmr1 gene generated the first mouse model for the fragile X syndrome [16]. Although this mutation is not representative of the CGG repeat expansion, it does cause loss of FMRP production, so the result is the same in the animal model as in patients.
Morphological abnormalities of the fragile X knockout mouse model
Morphological abnormalities in male fragile X patients include an elongated face with prominent ears and macroorchidism. In the fragile X mouse model, no facial abnormalities were observed [16], but macroorchidism is significant from day 15 after birth onwards (Fig. 2), and the increase in size compared with wild type exceeds 30% at 6 months 16, 17, 20, 27, 29, 32. No structural testicular abnormalities were observed in the mice 16, 33, similarly to human patients [4], and the macroorchidism is
Electrophysiogical abnormalities might relate to the cognitive deficits
Differences in spatial memory as measured in the Morris water maze test have been associated with abnormalities in long-term potentiation (LTP). LTP is a long lasting increase in synaptic efficiency, believed to be involved in learning and memory [45]. Four independent electrophysiological studies, each using a slightly different protocol, showed no evidence for altered LTP in the CA1 region of the hippocampus of the knockout mouse 19, 46, 47, 48. By contrast, LTP appeared severely reduced when
Fragile X knockout mice are prone to epileptic seizures
Seizures occur in 22% of fragile X patients [2]. However, spontaneous seizures were never observed in fragile X knockout mice, although they can be elicited by auditory stimuli. Fragile X knockout mice were more prone to epileptic seizures than their control littermates 30, 52. The susceptibility to seizures appears age dependent, with older mice showing a higher susceptibility. Seizure induction by chemical convulsants was not successful, suggesting that the increase in seizure susceptibility
Differences between human and mouse studies: the effect of genetic background
The original fragile X mouse model was generated in a 129P2 background and was subsequently bred into two different genetic backgrounds, C57BL/6 and FVB. The variation among results from the same test methods could be due to differences in the background mouse strains. In addition, early studies were carried out before the strains were fully congenic, while they still contained varying amounts of the 129P2 background. For example, the IIPMF field was large when measured in a C57BL/6 background,
Mouse models of repeat expansion
Expansion of the repeat from generation to generation is a poorly understood phenomenon of dynamic mutations in general. Experimental evidence suggests that expansion from a pre-mutation allele to a full-sized mutation allele in fragile X syndrome occurs during oogenesis or in the first days of postzygotic development [6]. However, many questions on the behavior of the repeat remain unanswered, including why male germ cells are spared from the expansion to a full mutation [5]. As these
Double knockouts with paralogous genes might unravel hidden deficits
The FMR1 gene is a member of a gene family, and one possible explanation for the relatively mild phenotype of the fragile X syndrome is that the protein products of two autosomal paralogs of FMR1 (FXR1 and FXR2) partially compensate for FMRP. This hypothesis predicts that double or triple knockouts of FMR1, FXR1 and FXR2 will show a much more severe phenotype than knockouts of each individual gene. Although an FXR1 knockout was created several years ago, not much is known about its phenotype
Rescue of the fragile X mutation
To determine whether the fragile X syndrome is a potentially treatable disorder, several attempts have been made to rescue the silenced murine Fmr1 gene using a transgenic human FMR1 gene. Initial attempts introduced a human cDNA under control of a CMV promoter into the knockout mouse [20]. Although the overall brain FMRP was about half of that of the controls, no rescue of the phenotype was observed. This could be the consequence of the cDNA being under control of a CMV promoter, which
The fragile X syndrome could be the caused by a generalized, mild brain dysfunction
Summarizing the differences between fragile X mutant mice and controls, it seems unlikely that the cognitive problems in the fragile X mouse are caused by deficits of a single, specific brain region (Table 2, Fig. 3). Abnormalities in the spatial learning point to hippocampal abnormalities and a crucial role of this brain region is also supported by the anatomical differences in hippocampal IIPMF fields and the altered long-term synaptic plasticity. However, the differences in acoustic startle
Acknowledgments
I thank Ben Oostra and Guy Van Camp for critical reading of the manuscript, and Annemie Van der Linden for generating the MRI image. Financial support for fragile X research in Antwerp was obtained through grants of the Belgian National Fund for Scientific Research – Flanders (FWO), an Interuniversity Attraction Pole (IUAP-V), and the Fragile X Research Foundation (FRAXA).
References (60)
Fragile X syndrome at the turn of the century
Mol. Med. Today
(2000)Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome
Cell
(1991)Absence of expression of the FMR-1 gene in fragile X syndrome
Cell
(1991)- et al.
Advances in understanding of fragile X pathogenesis and FMRP function, and in identification of X linked mental retardation genes
Curr. Opin. Genet. Dev.
(2002) Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome
Cell
(2001)Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function
Cell
(2001)Mildly impaired water maze performance in male Fmr1 knockout mice
Neuroscience
(1997)Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function
Neuroscience
(1999)Fmr1 knockout mouse has a distinctive strain-specific learning impaiment
Neuroscience
(2000)Spatial learning, contextual fear conditioning and conditioned emotional response in Fmr1 knockout mice
Behav. Brain Res.
(2000)
Molecular mechanisms of memory acquisition, consolidation and retrieval
Curr. Opin. Neurobiol.
The neurobiology of startle
Prog. Neurobiol.
Alterations in the auditory startle response in Fmr1 targeted mutant mouse models of fragile X syndrome
Brain Res.
Fragile X mice develop sensory hyperreactivity to auditory stimuli
Neuroscience
Dendritic spine pathology: cause or consequence of neurological disorders?
Brain Res. Brain Res. Rev.
Reduced cortical synaptic plasticity and GluR1 expression associated with Fragile X mental retardation protein deficiency
Mol. Cell. Neurosci.
Drosophila fragile X-related gene regulates the MAP1B homolog futsch to control synaptic structure and function
Cell
Fragile X (fmr1) mRNA expression is differentially regulated in two adult models of activity-dependent gene expression
Brain Res. Mol. Brain Res.
Long uninterrupted CGG repeats within the first exon of the human FMR1 gene are not intrinsically unstable in transgenic mice
Genomics
Physical and behavioral phenotype
Post-mortem examination of two fragile X brothers with an FMR1 full mutation
Am. J. Med. Genet.
The full mutation in the FMR-1 gene of male fragile X patients is absent in their sperm
Nat. Genet.
Characterization of the full fragile X syndrome mutation in fetal gametes
Nat. Genet.
Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells
Nat. Genet.
A decade of molecular studies of fragile X syndrome
Annu. Rev. Neurosci.
Targeting fragile X
Genome Biol.
The fragile X mental retardation protein binds specifically to its mRNA via a purine quartet motif
EMBO J.
Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation
Proc. Natl. Acad. Sci. U. S. A.
Fmr1 knockout mice: a model to study fragile X mental retardation
Cell
Transgenic mouse model for the fragile X syndrome
Am. J. Med. Genet.
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