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* * * * * * * * * * * * * * * * * * * * * * * * * * Huntington’s Disease 5’UTR 3’UTR 5’UTR 3’UTR CAG repeat, 28 copies (CAG)n QQQQ A string of glutamines in the protein Huntingtin PolyGlutamine or PolyQ The result of this repeat mutation If the expansion occurs in a coding region the result is usually gain of function for the protein The protein has an altered function as it now has a whole bunch of amino acids added to the code Example is Huntington’s disease Fragile X syndrome (FRAXA) One of the most common inheritable forms of mental retardation The fragile X syndrome (FRAXA) results from multiple copies of the sequence CGG (the expansion) in the 5’ UTR of the fragile X syndrome gene, FMR1 Results in gene silencing of the FMR1 gene product, FMRP. FMRP: the protein product of the FMR Fragile X syndrome The number of repeats is very important to the final severity of the disease. 5 – 50 copies has no effect, 50 – 200 results in an intermediate and distinct syndrome, fragile X tremor/ataxia (FXTAS) 200 copies gives rise to the full blown mutation. RNA binding domain Nuclear Localisation signal (NLS) 5’ 3’ 200 nt (full mutation) 50 – 200 nt 50 nt (CGG)n FMRP N C Gene FMR1 FMRP: the protein product of the FMR1 gene It is located largely in the cytoplasm but does make excursions to the nucleus. It has 3 RNA binding domains; it associates with ribosomes and seems to be involved in translational regulation of a group of RNA targets. FMRP: the protein product of the FMR1 gene The protein and its mRNA localise in dendritic spines. The protein binds to certain “target” RNA species and represses translation. These are thought to be mRNAs coding for proteins involved in neuronal development, synaptic transmission and cytoskeleton Huntington’s disease “George Huntington (1850-1916) described the condition while working as a newly qualified doctor in the rural general practice of his father and grandfather on Long Island, New York State. Together their observations cov