Dynamic mutations are an important mutation class Describe - cmgs动态突变的一个重要突变类描述CMGS.pptVIP

Dynamic mutations are an important mutation class. Describe the full range of methods and strategies that are currently being used to diagnose 3 inherited diseases of your choice. Choose examples which maximise the number of methods and strategies you describe.Sarah Waller Key words: Trinucleotide repeat; Huntington disease; polyglutamine; myotonic dystrophy; Fragile X syndrome; Southern blot; triplet-primed PCR; exclusion testing. Useful reference: La Spada Taylor, Nat Rev Genet 11:247 (2010) Dynamic mutations A dynamic mutation is an unstable heritable element, where the initial change to the DNA sequence alters the chance of further changes to it. These mutations typically occur in areas of tandem repeats, and are exemplified in the trinucleotide repeat disorders. Triplet expansion is caused by slippage during DNA replication. ‘Loop out’ structures may form during DNA replication due to the repetitive nature of these DNA sequences; if this occurs on the daughter strand the number of repeats will be increased. If the loop out structure occurs on the parent strand the number of repeats can decrease and the mutation can revert to a normal or premutation carrier state. Trinucleotide repeat disorders The length of the repeat determines the probability and extent of its pathogenicity. Anticipation – the tendency of the age of onset to decrease and the severity of symptoms to increase through successive generations due to continued repeat expansion. More common in paternal transmission due to instability of the CAG repeat in spermatogenesis. Most of these diseases have neurological symptoms. Methods strategies currently in use to diagnose: Huntington disease Myotonic dystrophy Fragile X syndrome Huntington disease (HD) HD is a progressive neuronal degenerative disease caused by expansion of a CAG repeat in exon 1 of the HTT gene, resulting in production of a toxic protein containing a polyglutamine repeat. Pathogenicity of HD allele is determined by its size: