Abstract
Allele-specific silencing using small interfering RNAs targeting heterozygous single-nucleotide polymorphisms (SNPs) is a promising therapy for human trinucleotide repeat diseases such as Huntington's disease. Linking SNP identities to the two HTT alleles, normal and disease-causing, is a prerequisite for allele-specific RNA interference. Here we describe a method, SNP linkage by circularization (SLiC), to identify linkage between CAG repeat length and nucleotide identity of heterozygous SNPs using Huntington's disease patient peripheral blood samples.
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Acknowledgements
We thank M. Chan for advice on lymphocyte isolation and culture, J. Straubhauer (NIH Diabetes and Endocrinology Research grant 5P30DK32520-25) for assistance with data analysis, members of Zamore and Aronin labs for helpful discussions, assistance and comments on the manuscript. US National Institutes of Health (NS38194 to N.A., P.D.Z. and M. DiFiglia; 1P01NS058793 to H.D.R. and S.H.; and National Institute of Neurological Disorders and Stroke NS042861 to H.D.R.) and CHDI, Inc. (N.A. and P.D.Z.) supported this work.
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H.D.R., S.H. and J.-H.C. obtained Huntington's disease patient peripheral blood samples. W.L. performed the majority of the laboratory experiments. L.A.K. examined SNP heterozygosity using genomic DNA extracted from patient lymphocytes. P.D.Z. proposed the circularization strategy. W.L., P.D.Z. and N.A. designed the study and prepared the manuscript.
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Supplementary Tables 1–4, Supplementary Methods (PDF 185 kb)
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Liu, W., Kennington, L., Rosas, H. et al. Linking SNPs to CAG repeat length in Huntington's disease patients. Nat Methods 5, 951–953 (2008). https://doi.org/10.1038/nmeth.1261
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DOI: https://doi.org/10.1038/nmeth.1261
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