Human Molecular Genetics Advance Access published online on April 4, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm054
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street, Charlestown MA 02129-4404, USA 3 Program in Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089-2910 USA 4 Department of Pathology, University of Southern California, Los Angeles, California 90089-2910 USA 5 Department of Pathology and New York Brain Bank, University College of Physicians and Surgeons, New York, New York, 10032 USA 6 Department of Neurology and Psychiatry and the Hereditary Disease Foundation and Columbia, University College of Physicians and Surgeons, New York, New York, 10032 USA
* To whom correspondence should be addressed. Tel: 213-740-7675; Fax: 213-821-1123; email: arnheim{at}usc.edu
Received October 25, 2006; Revised March 1, 2007; 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 striatum than in 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 to 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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Swami, A. E. Hendricks, T. Gillis, T. Massood, J. Mysore, R. H. Myers, and V. C. Wheeler Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset Hum. Mol. Genet., August 15, 2009; 18(16): 3039 - 3047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gray, D. I. Shirasaki, C. Cepeda, V. M. Andre, B. Wilburn, X.-H. Lu, J. Tao, I. Yamazaki, S.-H. Li, Y. E. Sun, et al. Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice J. Neurosci., June 11, 2008; 28(24): 6182 - 6195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Gonitel, H. Moffitt, K. Sathasivam, B. Woodman, P. J. Detloff, R. L. M. Faull, and G. P. Bates DNA instability in postmitotic neurons PNAS, March 4, 2008; 105(9): 3467 - 3472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Claassen and R. S. Lahue Expansions of CAG{middle dot}CTG repeats in immortalized human astrocytes Hum. Mol. Genet., December 15, 2007; 16(24): 3088 - 3096. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Lin and J. H. Wilson Transcription-Induced CAG Repeat Contraction in Human Cells Is Mediated in Part by Transcription-Coupled Nucleotide Excision Repair Mol. Cell. Biol., September 1, 2007; 27(17): 6209 - 6217. [Abstract] [Full Text] [PDF]
|
|