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. 2022 Oct 10;7(19):e141042. doi: 10.1172/jci.insight.141042

Figure 2. PAM-altering SNPs (PAS) that permit mutant HTT-specific NMD-CRISPR/Cas9 in HD.

Figure 2

(A) In order to identify PAM sites that allow mutant-specific CRISPR/Cas9 in HD, PAS on HTT coding exons were identified from KGP data. Subsequently, PAS-generated NGG PAM sites were mapped to the 8 common HTT haplotypes. Among 91 exonic PAS on HTT, alleles of 3 exonic PAS (arrows) are polymorphic in the 8 common HTT haplotypes, permitting mutant-specific CRISPR/Cas9 in European HD subjects with common diplotypes. (B) To estimate the levels of mutant specificity of those 3 polymorphic PAS, we calculated the proportion of each diplotype in HD subjects with European ancestry, focusing on the 8 common haplotypes. Percentage values for the most frequent haplotypes in the disease and normal chromosomes (hap.01 and hap.08) are provided. (C) We identified HTT diplotypes carrying mutant-specific PAM sites generated by those 3 polymorphic PAS and calculated the levels of mutant specificities. Table cells in blue, red, and green represent the NGG PAM site on the mutant HTT generated by rs1065745, rs363099, and rs362331, respectively.