Genotype-phenotype relationships in fragile X associated disorders

Fragile X Syndrome is the most common inherited form of severe neurodevelopmental abnormality, and it is caused by a large expansion of the trinucleotide (CGG) repeat in the X-linked (FMR1) gene. This large expansion leads to silencing the gene and depletion of specific protein (FMRP), which is important in synaptic plasticity. Small expansions of the CGG repeat lead to some other abnormal conditions occurring in adults, including early menopause in females, and a spectrum of neurodegenerative disorders, including Fragile X–Associated Tremor Ataxia Syndrome (FXTAS), predominantly in males. These late onset disorders have been linked to the elevated level of the FMR1 gene transcript, mRNA, but the mechanisms of a toxicity of this elevated transcript to brain cells and other tissues have not yet been fully explained.

This project aims to elucidate the mechanisms leading from the wide range of CGG repeat expansions to neuropsychological and clinical manifestations in carriers of these expanded FMR1 alleles. The study, which has been conducted for more than a decade, has been supported by the National Institutes of Health USA (NIH) series of grants to Dr Danuta Loesch, and it involves collaboration with the Murdoch Research Institute, and several neurology clinics in Victoria and some other states. By relating the severity and type of clinical manifestations and neuropsychological deficits to a range of changes in the FMR1 gene, as well as several cellular markers, we will be able to understand  how these deficits occur, why they occur in some carriers and not in the others, and thus how they may be prevented or treated.