Human Molecular Genetics Advance Access originally published online on April 4, 2007
Human Molecular Genetics 2007 16(10):1133-1142; doi:10.1093/hmg/ddm054
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Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain
1 Division of Molecular Genetics, University of Glasgow, 56 Dumbarton Road, Glasgow G11 6NU, UK, 2 Massachusetts General Hospital and Harvard Medical School, Mass General Institute for Neurodegenerative Disease, 114, 16th Street, Charlestown, MA 02129-4404, USA, 3 Program in Molecular and Computational Biology and 4 Department of Pathology, University of Southern California, Los Angeles, CA 90089-2910, USA, 5 Department of Pathology and New York Brain Bank and 6 Departments of Neurology and Psychiatry and 7 Hereditary Disease Foundation and Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
* To whom correspondence should be addressed. Tel: +1 2137407675; Fax: +1 2138211123; Email: arnheim{at}usc.edu
Received October 25, 2006; Accepted March 1, 2007
Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Here, we provide evidence supporting the hypothesis that somatic increases of mutation length play a role in the progressive nature and cell-selective aspects of HD pathogenesis. Results from micro-dissected tissue and individual laser-dissected cells obtained from human HD cases and knock-in HD mice indicate that the CAG repeat is unstable in all cell types tested although neurons tend to have longer mutation length gains than glia. Mutation length gains occur early in the disease process and continue to accumulate as the disease progresses. In keeping with observed patterns of cell loss, neuronal mutation length gains tend to be more prominent in the striatum than in the cortex of low-grade human HD cases, less so in more advanced cases. Interestingly, neuronal sub-populations of HD mice appear to have different propensities for mutation length gains; in particular, smaller mutation length gains occur in nitric oxide synthase-positive striatal interneurons (a relatively spared cell type in HD) compared with the pan-striatal neuronal population. More generally, the data demonstrate that neuronal changes in HD repeat length can be at least as great, if not greater, than those observed in the germline. The fact that significant CAG repeat length gains occur in non-replicating cells also argues that processes such as inappropriate mismatch repair rather than DNA replication are involved in generating mutation instability in HD brain tissue.
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