The Molecular Basis of FXTAS

The FMR1 gene, located on the X chromosome, harbours a CGG-trinucleotide repeat in a DNA region that is transcribed into RNA, but is not translated into protein. In 1991 it was discovered that this CGG repeat ((CGG)n) can vary in length, since it is unstable upon transmission to the next generation. A length exceeding 200 CGGs turned out to be responsible for fragile X syndrome, which presents itself as mental retardation. This (CGG)n is one of the first trinucleotide repeats identified to be the genetic cause of a neurological disorder. In humans, the (CGG)n in the FMR1 gene is between 5 and 55 CGGs long in the normal population. Both the FMR1 promoter region and the (CGG)n become methylated when the (CGG)n exceeds 200 trinucleotides (full mutation: FM),. This results in inactivation of the gene, thus preventing the protein product FMRP from being synthesised. FMRP regulates transport and translation of certain mRNA molecules in neural processes. By affecting the plasticity of synapses (the space between two neurons where signal transduction takes place) in these dendrites, FMRP plays an important role in learning and memory processes. The absence of FMRP in fragile X patients therefore results in mental retardation.

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