Human Molecular Genetics Advance Access originally published online on September 19, 2007
Human Molecular Genetics 2007 16(24):3088-3096; doi:10.1093/hmg/ddm270
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Expansions of CAG·CTG repeats in immortalized human astrocytes
1 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, PO Box 986805, Omaha, NE 68198-6805, USA, 2 Department of Biochemistry, National University of Ireland, Galway, Ireland
* To whom correspondence should be addressed. Tel: +353 91495756; Fax: +353 91495504; Email: bob.lahue{at}nuigalway.ie
Received July 15, 2007; Accepted September 14, 2007
Expansions of trinucleotide repeats (TNRs) are the genetic cause for a number of neurodegenerative disorders. In some of these diseases, ongoing somatic expansions in the brain are thought to contribute to disease progression. Expansions can occur in both neurons and supporting glial cells, but little is known about molecular mechanisms of expansion in these cells, particularly glia. To help address this issue, a cultured human astrocyte cell line called SVG-A was tested for expansions of CAG•CTG repeats present on a shuttle vector. A quantitative genetic selection showed that +4 to +15 repeat expansions occur readily for starting alleles of 25 repeats, thereby spanning the important boundary between short stable repeats and longer more unstable CAG•CTG tracts. These expansions in glial cell culture, as in humans, were sequence and length-dependent, and were inhibited by the presence of a sequence interruption within the triplet repeat tract. These findings suggest that the mutations seen in cell culture reflect at least some of the in vivo expansions seen in glia. Mechanistically, it was found that the direction of DNA replication through the TNR influenced the frequency of expansions, suggesting that either replication or a replication-associated process, such as DNA repair, contributes to CAG•CTG tract instability in SVG-A cells. This finding is consistent with the idea that replication-based mechanisms can be a source of TNR expansions in astrocytes, which, unlike neurons, retain proliferative capacity throughout life.
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