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. 2016 Mar 22;5(3):e297. doi: 10.1038/mtna.2016.7

Figure 1.

Figure 1

Design of therapeutic miHTT variants for Huntington's disease (HD) therapy. (a) Schematic of exons 1, 50, and 67 (extended to 3'UTR) of human wild-type (wt) or mutated (mt) huntingtin (HTT) gene (gb|L12392.1|HUMHDA) with CAG expansions in black, target sequences for miH1-miH21 in yellow, miSNP50 variants in green, and miSNP67 variants in blue. Single-nucleotide polymorphisms (SNPs) located either in exon 50 (rs362331) or exon 67 extended to 3'UTR (rs362307) are represented as dark stripes within the target regions. (b) The engineered mmu-pre-miR-155 scaffold used for miHTT expression with highlighted 21 nt guide strand. (c) Twenty-one miHTT variants were designed to target HTT exon 1. In a consecutive manner, miH1-miH21 bind to HTT exon 1 shown in yellow with the target starting nucleotide positions in gray. (d) miSNP50C variants targeting the C isoform of mtHTT-associated SNP rs362331 in exon 50. Micro-shifting of mature miSNP50C sequences along the C isoform generated 21 variants with the SNP-matching position 1–21 (miSNP50C-1—miSNP50C-21). The C isoform is represented in dark green and the SNP-matching nucleotide in light green. (e) miSNP50T variants targeting the T isoform of mtHTT-associated SNP rs362331 in exon 50. miSNP50T variants were generated similarly to miSNP50C. (f) miSNP67T variants targeting the T isoform of mtHTT-associated SNP rs362307 in exon 67. miSNP67T variants were generated similarly to miSNP50T. The T isoform of rs362307 is represented in dark blue and the SNP-matching nucleotide in light blue. A list of all pre-miHTT scaffolds can be found in Supplementary Table S1.