Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics
ABSTRACT Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families.
- SourceAvailable from: Corrado Romano[Show abstract] [Hide abstract]
ABSTRACT: Typical Xq25 duplications are large and associated with heterogeneous phenotypes. Recently, small duplications involving this genomic region and encompassing the GRIA3 and STAG2 genes have been reported. These Xq25 microduplications are associated with a recognizable syndrome including intellectual disability and distinctive facial appearance. We report on Xq25 microduplications in two unrelated families identified by array comparative genomic hybridization. In both families, the genomic imbalances segregated with the disease in male individuals, while the phenotypes of the heterozygous females appeared to be modulated by their X-inactivation pattern. These rearrangements of about 600 kb involved only three genes: THOC2, XIAP, and STAG2. Further characterization by FISH analyses showed tandem duplication in the Xq25 locus of these genes. These data refine the Xq25 candidate region, identifying a minimal duplicated region of about 270 kb encompassing the XIAP and STAG2 genes. We discuss the function of the genes in the rearrangements and their involvement in the pathogenesis of this disorder. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 08/2014; 164A(8). DOI:10.1002/ajmg.a.36570 · 2.05 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Fragile X syndrome is a neurodevelopmental disorder caused by a trinucleotide repeat expansion in the FMR1 gene that codes for Fragile X Mental Retardation Protein (FMRP). To determine if FMRP expression in the central nervous system could reverse phenotypic deficits in the Fmr1 knockout mouse model of fragile X, we used a single-stranded adeno-associated viral vector (AAV) with viral capsids from serotype 9 that contained a major isoform of FMRP. FMRP transgene expression was driven by the neuron-selective synapsin-1 promoter. The vector was delivered to the brain via a single bilateral intra-cerebroventricular injection into neonatal Fmr1 knockout mice and transgene expression and behavioral assessments were conducted 22-26 and 50-56 days post-injection. Western blotting and immunocytochemical analyses of AAV-FMRP injected mice revealed FMRP expression in the striatum, hippocampus, retrosplenial cortex and cingulate cortex. Cellular expression was selective for neurons and reached approximately 50% of wild-type levels in the hippocampus and cortex at 56 days post-injection. The pathologically elevated repetitive behavior and the deficit in social dominance behavior seen in PBS-injected Fmr1 knockout mice were reversed in AAV-FMRP injected mice. These results provide the first proof-of-principle that gene therapy can correct specific behavioral abnormalities in the mouse model of fragile X syndrome.Neuropsychopharmacology accepted article preview online, 07 July 2014; doi:10.1038/npp.2014.167.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2014; 39(13). DOI:10.1038/npp.2014.167 · 7.83 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Neuronal dendrites are structurally and functionally dynamic in response to changes in afferent activity. The fragile X mental retardation protein (FMRP) is an mRNA binding protein that regulates activity-dependent protein synthesis and morphological dynamics of dendrites. Loss and abnormal expression of FMRP occur in fragile X syndrome (FXS) and some forms of autism spectrum disorders. To provide further understanding of how FMRP signaling regulates dendritic dynamics, we have examined dendritic expression and localization of FMRP in the reptilian and avian nucleus laminaris (NL) and its mammalian analogue, the medial superior olive (MSO), in rodents and humans. NL/MSO neurons are specialized for temporal processing of low frequency sounds for binaural hearing, which is impaired in FXS. Protein BLAST analyses first demonstrate that the FMRP amino acid sequences in the alligator and chicken are highly similar to human FMRP with identical mRNA-binding and phosphorylation sites, suggesting that FMRP functions similarly across vertebrates. Immunocytochemistry further reveals that NL/MSO neurons have very high levels of dendritic FMRP in low frequency hearing vertebrates including alligator, chicken, gerbil, and human. Remarkably, dendritic FMRP in NL/MSO neurons often accumulates at branch points and enlarged distal tips, loci known to be critical for branch-specific dendritic arbor dynamics. These observations support an important role for FMRP in regulating dendritic properties of binaural neurons that are essential for low frequency sound localization and auditory scene segregation, and support the relevance of studying this regulation in nonhuman vertebrates that use low frequencies in order to further understand human auditory processing disorders. J. Comp. Neurol., 2013. © 2013 Wiley Periodicals, Inc.The Journal of Comparative Neurology 06/2014; 522(9). DOI:10.1002/cne.23520 · 3.51 Impact Factor