Researchers at the University Nebraska Medical Center (UNMC) have developed a sensitive and quantitative assay for the screening of trinucleotide repeat (TNR) mutations.  The assay system involves the transfer of a DNA shuttle vector between mammalian and yeast cells.  TNR mutations generated during mammalian cell culture are revealed by transfer of the vector to yeast followed by genetic analysis. Expansions of specific DNA trinucleotide repeats (TNR) are the cause of an increasing number of hereditary disorders in humans.  Specifically, the pathological expansion of unstable repeats is known to cause 14 neurological diseases. In some diseases, such as Huntington’s, the repetitive DNA sequences are translated into long tracts of the same amino acid (usually glutamine), which alters interactions with cellular constituents and leads to the development of disease.  For other disorders, including common genetic disorders such as myotonic dystrophy and fragile X syndrome, the DNA repeat is located in noncoding regions of transcribed sequences and disease is probably caused by altered gene expression.  The diagnosis of these diseases can be made by detection of the TNR known to be associated with the disease.  However, further advances in risk assessment for, diagnosis of, and development of potential therapies for these diseases will be greatly facilitated by selective, genetic assays for TNR mutations. Current methods for detection of TNR and subsequent diagnosis of disease are non-selective and non-quantitative.  The major advantage of this invention is to provide a selective and quantitative genetic means to measure expansions and contractions of trinucleotide repeat tracts.  This advantage allows its application to the field of predictive toxicology.  The ongoing development of the assay will enable its use as a means of assessing the risk of TNR mutations that is associated with a particular compound. Importantly, the selective and quantitative aspects of this assay system will also enable its further development as a mechanism for screening compounds, agents or small molecules, which are directed at inhibiting further expansion (or stimulating contraction) of TNR regions that are associated with disease. 

Patent Issued  (TID - 99)

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