Fragile X syndrome causes
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Causes
The fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. (Incidence of the disease itself is about 1 in every 4000 females.)
FMR1 is divided into four allelic classes based on the number of CGG repeats present in the 5' untranslated region (5'UTR): 1.) Common alleles with 40 or less repeats 2.) Intermediate alleles with 41-54 repeats 3.) Premutation alleles with 55-200 repeats 4.) Full mutation alleles with greater than 200 repeats. Common, intermediate, and premutation alleles are normally unmethylated in the 5'UTR and FMR1 is transcriptionally active. Premutation alleles often have increased transcriptional activity. Full mutation alleles are usually hypermethylated in the 5'UTR and transcriptionally inactive.[1]
This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears 'fragile' under the microscope at that point, a phenomenon that gave the syndrome its name.
Mutation of the FMR1 gene leads to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. FMRP serves as a counterbalance to protein synthesis induced by group 1 metabotropic glutamate receptor (mGluR) activation. The mGluR1 and mGluR5 proteins participate in cell signaling pathways that upregulate the expression of proteins involved in diverse neuronal functions such as dendritic spine elongation, fear memory (possibly correlated to autism), and long-term potentiation of the corticostriatal synapse (possibly correlated to obsessive-compulsive behavior).[2] mGluR signaling in FMRP deficient cells is associated with increased alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) uptake. The trafficking of AMPAR to and from synaptic membranes is thought to be essential to the synaptic processes involved in memory and learning. Unbalanced AMPAR trafficking may underlie the abnormal cognition seen in FXS patients and patients with other cognitive disorders, such as Alzheimer’s disease and schizophrenia.[3]
References
- ↑ Garber KB, Visootsak J, and Warren ST (2008) "Fragile X Syndrome". European Journal of Human Genetics 16: 666-672.
- ↑ GBear MF, Huber KM, Warren ST (2004) "The mGluR theory of fragile X mental retardation". Trends in Neurosciences 27: 370-377.
- ↑ Nakamoto M, Nalavadi V, Epstein MP, Narayanan U, Bassell GJ, Warren ST (2007) "Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors". Neuroscience 104: 15537-15542.