Oligogenic inheritance of a human heart disease involving a genetic modifier

被引：134

作者：

Gifford, Casey A. ^{[1
,2
]}

Ranade, Sanjeev S. ^{[1
,2
]}

Samarakoon, Ryan ^{[1
,2
]}

Salunga, Hazel T. ^{[1
,2
]}

de Soysa, T. Yvanka ^{[1
,2
]}

Huang, Yu ^{[1
]}

Zhou, Ping ^{[1
]}

Elfenbein, Arye ^{[1
,2
]}

Wyman, Stacia K. ^{[1
,6
]}

Bui, Yen Kim ^{[1
,2
]}

Metzler, Kimberly R. Cordes ^{[1
,2
]}

Ursell, Philip ^{[3
]}

Ivey, Kathryn N. ^{[1
,2
,4
,5
,7
]}

Srivastava, Deepak ^{[1
,2
,4
,5
]}

机构：

[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

来源：

SCIENCE | 2019年 / 364卷 / 6443期

关键词：

TRANSCRIPTION FACTORS; CARDIAC TRANSCRIPTION; FUNCTIONAL ASSAYS; PROTEIN; NKX2-5; CARDIOMYOPATHY; ACTIVATION; EXPRESSION; MUTATIONS; REGULATOR;

D O I：

10.1126/science.aat5056

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页码：865 / +

页数：24

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