Oligogenic inheritance of a human heart disease involving a genetic modifier
Oligogenic inheritance of a human heart disease involving a genetic modifier
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DOI：
10.1126/science.aat5056
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发表时间：
2019-05-31
期刊：
影响因子：
56.9
通讯作者：
Srivastava, Deepak
中科院分区：
文献类型：
--
作者：
Gifford, Casey A.;Ranade, Sanjeev S.;Srivastava, Deepak
复杂的遗传机制被认为是许多人类疾病的基础，但这种模型的实验证据一直难以捉摸。在这里，我们表明，人类心脏异常可能是由罕见的，遗传性杂合突变的组合。一个核心家族的全外显子组测序显示，三个儿童期发病的心肌病后代遗传了MKL 2、MYH 7和NKX 2 -5基因中的三个错义单核苷酸变异。MYH 7和MKL 2变异体遗传自患病的无症状父亲，罕见的NKX 2 -5变异体（次要等位基因频率，0.0012）遗传自未患病母亲。我们使用CRISPR-Cas9来产生编码直链淀粉变体的小鼠，并发现所有三种变体的复合杂合性重现了人类疾病表型。对小鼠心脏和人类诱导多能干细胞衍生的心肌细胞的分析为NKX 2 -5变体作为遗传修饰剂的贡献提供了组织学和分子证据。
Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell-derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant's contribution as a genetic modifier.