Repeat Expansion
One effort of the lab is focused on genomic instability and how it relates to neuromuscular disease and cancer. Repetitive sequences, also called microsatellites, occur throughout the human genome. Instability of these repeats is associated with many neuromuscular diseases and cancers. Microsatellites are composed of tandemly arrayed, identical repeats of a usually short simple sequence such as the triplet d(GAA)n (abbreviated as GAA). Expansions of particular repeats during their transmission from parent to child have been tightly associated with more than thirty repeat expansion hereditary neuromuscular and neurodegenerative diseases, including Friedreich's ataxia (GAA/TTC), myotonic dystrophy (CAG/CTG and CAGG/CCTG), Huntington's disease (CAG/CTG), and Fragile X syndrome (GCC/GGC). Studies from our lab have shown the ability to induce massive expansions during DNA replication in vitro, enabling us to study the expansion intermediates. We found that GAA expansions form large growing hairpin structures able to protect the expansions from DNA repair; and DNA damage induced large expansions of AAT and ATT tracts. Recent studies are focused on the essential replication protein human flap endonuclease 1, which has been implicated in repeat instability and tumor progression.

Molecular Mechanisms of Ataxia
Another effort of the lab is aimed at understanding how the repeat expansions cause disease. We are particularly interested in the subset of repeats located in introns and untranslated regions of their host genes. For example, the expanded repeats in myotonic dystrophy are transcribed to produce gain-of-function or “toxic” RNAs, which bind proteins to disturb splicing. One result is alterations in the ion channels necessary for nerve function. We are actively studying how other repeat expansions result in ataxia. Contrasting hypotheses are being tested: the first is that a gain-of-function RNA is responsible for the ataxia phenotypes, the second is that the expanded RNA interferes with its own translation resulting in a loss of expression of the host genes.

Selected Publications