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Keywords Associated with Work
DNA Repeat Expansion
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Friedreich Ataxia
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Huntington Disease
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Neurodegenerative Diseases
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Spinocerebellar Ataxias
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Translational Research
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Trinucleotide Repeat Expansion
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Primary Research / Clinical / Teaching Interests
DNA Mismatch Repair
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DNA Repeat Expansion
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Friedreich Ataxia
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Huntington Disease
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Secondary Research / Clinical / Teaching Interests
MLH3 (MutL Protein Homolog 3)
A minor mismatch repair protein subunit called MLH3 selectively cuts DNA in a way that causes DNA repeats to expand. MLH3 is expressed as two isoforms via alternative splicing in human tissue, isoform one causes DNA repeat expansion but isoform two does not.
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Unique Equipment Used
Oxford Nanopore MinION Molecular Sequencer
The Oxford Nanopore MinION uses nanopores connected to sensor chips to measure disruption of current as a DNA or RNA molecule traverses the pore to determine the sequence. The molecular pore technique can sequence a DNA molecule over a million bases long. Whereas the short reads generated by "Next gen" sequencing are all but useless for tandem repeats. PCR-free sequencing of native DNA or RNA also provides base modification data such as DNA methylation.
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Unique Techniques Used or Developed
Therapeutic splice redirection of MLH3 isoforms
MutL-gamma, a minor mismatch repair component comprised of MLH1-MLH3 heterodimers, is the active agent in DNA repeat expansion. We showed that MLH3 isoform 1 contributes to DNA repeat expansion, but that MLH3 isoform 2 does not. The two isoforms differ by one small exon, and exclusion of this exon by oligonucleotide mediated splice redirection can slow or stop DNA repeat expansion. As a therapeutic approach, MLH3 splice redirection has the potential to treat many if not all the DNA repeat expansion disorders.
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