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DOI | 10.1126/science.aat5056 |
Oligogenic inheritance of a human heart disease involving a genetic modifier | |
Gifford, Casey A.1,2; Ranade, Sanjeev S.1,2; Samarakoon, Ryan1,2; Salunga, Hazel T.1,2; de Soysa, T. Yvanka1,2; Huang, Yu1; Zhou, Ping1; Elfenbein, Arye1,2; Wyman, Stacia K.1,6; Bui, Yen Kim1,2; Metzler, Kimberly R. Cordes1,2; Ursell, Philip3; Ivey, Kathryn N.1,2,4,5,7; Srivastava, Deepak1,2,4,5 | |
2019-05-31 | |
发表期刊 | SCIENCE |
ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2019 |
卷号 | 364期号:6443页码:865-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | 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. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000469887900057 |
WOS关键词 | TRANSCRIPTION FACTORS ; CARDIAC TRANSCRIPTION ; FUNCTIONAL ASSAYS ; PROTEIN ; NKX2-5 ; CARDIOMYOPATHY ; ACTIVATION ; EXPRESSION ; MUTATIONS ; REGULATOR |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/201531 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA; 2.Roddenberry Stem Cell Ctr Gladstone, San Francisco, CA 94158 USA; 3.Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA; 4.Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA; 5.Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA; 6.Innovat Genom Inst, Berkeley, CA 94704 USA; 7.Tenaya Therapeut, San Francisco, CA 94080 USA |
推荐引用方式 GB/T 7714 | Gifford, Casey A.,Ranade, Sanjeev S.,Samarakoon, Ryan,et al. Oligogenic inheritance of a human heart disease involving a genetic modifier[J]. SCIENCE,2019,364(6443):865-+. |
APA | Gifford, Casey A..,Ranade, Sanjeev S..,Samarakoon, Ryan.,Salunga, Hazel T..,de Soysa, T. Yvanka.,...&Srivastava, Deepak.(2019).Oligogenic inheritance of a human heart disease involving a genetic modifier.SCIENCE,364(6443),865-+. |
MLA | Gifford, Casey A.,et al."Oligogenic inheritance of a human heart disease involving a genetic modifier".SCIENCE 364.6443(2019):865-+. |
条目包含的文件 | 条目无相关文件。 |
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