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Human Molecular Genetics Advance Access originally published online on October 20, 2004
Human Molecular Genetics 2004 13(24):3057-3068; doi:10.1093/hmg/ddh325
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Human Molecular Genetics, Vol. 13, No. 24 © Oxford University Press 2004; all rights reserved

Somatic deletion events occur during early embryonic development and modify the extent of CAG expansion in subsequent generations

I.V. Kovtun1, A.R. Thornhill2 and C.T. McMurray1,3,4,*

1Department of Molecular Pharmacology and Experimental Therapeutics, 2Department of Obstetrics and Gynecology, 3Department of Biochemistry and Molecular Biology and 4Molecular Neuroscience Program, Mayo Clinic and Foundation, Rochester, MN 55905, USA

Received July 2, 2004; Revised September 29, 2004; Accepted October 11, 2004

Alterations in trinucleotide repeat length during transmission are important in the pathophysiology of Huntington's disease (HD). However, it is not well understood where, when and by what mechanism expansion occurs. We have followed the fate of CAG repeats during development in mice that can [hHD(–/+)/Msh2(+/+)] or cannot [hHD(–/+)/Msh2(–/–)] expand their repeats. Here we show that long repeats are shortened during somatic replication early in the embryo of the progeny. Our data point to different mechanisms for expansion and deletion. Deletions arise during replication, do not depend on the presence of Msh2 and are largely restricted to early development. In contrast, expansions depend on strand break repair, require the presence of Msh2 and occur later in development. Overall, these results suggest that deletions in early development serve as a safeguard of the genome and protect against expansion of the disease-range repeats during transmission.

* To whom correspondence should be addressed. Tel: +1 5072841597; Fax: +1 5072849111; Email: mcmurray.cynthia{at}mayo.edu


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