Haplotype-specific insertion-deletion variations for allele-specific targeting in Huntington's disease.
Haplotype-specific insertion-deletion variations for allele-specific targeting in Huntington's disease.
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DOI：
10.1016/j.omtm.2022.03.001
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发表时间：
2022-06-09
期刊：
影响因子：
--
通讯作者：
Lee JM
中科院分区：
文献类型：
--
作者：
Shin JW;Shin A;Park SS;Lee JM
亨廷顿氏病（HD）是一种显性遗传性神经退行性疾病，由亨廷顿蛋白（HTT） CAG重复扩增引起。考虑到HTT在HD的发展和临床表现时显著的神经退行性变中的重要作用，等位基因特异性药物的早期治疗是一种很有前途的策略。等位基因特异性反义寡核苷酸（ASO）靶向单核苷酸多态性（snp）的可行性已在HD模型中得到证实。在这里，我们构建了单倍型特异性插入-删除变异（indels）的图谱，以开发替代的突变型http特异性策略。我们将1000基因组计划数据中注释的HTT单倍型的索引映射到常见的HTT单倍型上，揭示了突变特异性HTT靶向的候选索引。随后对HD家族的测序确认了候选位点，并发现了额外的等位基因特异性索引。有趣的是，最常见的正常HTT单倍型在许多位点携带有大等位基因长度差异的索引，这进一步揭示了有希望的单倍型特异性靶标。当携带最常见HTT二倍型的患者来源细胞用靶向候选indels （rs772629195或rs72239206）突变等位基因的ASOs处理时，观察到完全的突变特异性。总之，我们的单倍型特异性索引图谱允许在HD受试者中识别等位基因特异性靶点，可能有助于开发适合HD早期治疗的安全的降低htt的治疗方法。等位基因特异性策略可能对亨廷顿舞蹈病产生显著的治疗效果。单核苷酸多态性已被广泛用于选择性靶向突变的亨廷顿蛋白。我们构建了单倍型特异性indel变异图谱，并在候选indel中显示出高水平的等位基因特异性，为替代等位基因特异性策略提供了遗传资源。
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in huntingtin (HTT). Given an important role for HTT in development and significant neurodegeneration at the time of clinical manifestation in HD, early treatment of allele-specific drugs represents a promising strategy. The feasibility of an allele-specific antisense oligonucleotide (ASO) targeting single-nucleotide polymorphisms (SNPs) has been demonstrated in models of HD. Here, we constructed a map of haplotype-specific insertion-deletion variations (indels) to develop alternative mutant-HTT-specific strategies. We mapped indels annotated in the 1000 Genomes Project data on common HTT haplotypes, revealing candidate indels for mutant-specific HTT targeting. Subsequent sequencing of an HD family confirmed candidate sites and revealed additional allele-specific indels. Interestingly, the most common normal HTT haplotype carries indels of big allele length differences at many sites, further uncovering promising haplotype-specific targets. When patient-derived cells carrying the most common HTT diplotype were treated with ASOs targeting the mutant alleles of candidate indels (rs772629195 or rs72239206), complete mutant specificity was observed. In summary, our map of haplotype-specific indels permits the identification of allele-specific targets in HD subjects, potentially contributing to the development of safe HTT-lowering therapeutics that are suitable for early treatment in HD. Allele-specific strategies may generate significant therapeutic benefits in Huntington's disease. Single-nucleotide polymorphisms have been widely used to selectively target the mutant huntingtin. We constructed a map of haplotype-specific indel variations and showed high levels of allele specificity in candidate indels, providing genetic resources for alternative allele-specific strategies.
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