Mutations in NOTCH1 cause aortic valve disease
Mutations in NOTCH1 cause aortic valve disease
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DOI：
10.1038/nature03940
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发表时间：
2005-09-08
期刊：
影响因子：
64.8
通讯作者：
Srivastava, D
中科院分区：
文献类型：
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作者：
Garg, V;Muth, AN;Srivastava, D
主动脉瓣钙化是成人心脏病的第三大原因(1)。发病率随着年龄的增长而增加，通常与1-2%的人群中存在的二尖瓣相关(2)。尽管频率很高，但瓣膜钙化的机制和两瓣而不是三瓣的发育起源尚不清楚。在这里，我们表明，信号和转录调节因子NOTCH1的突变导致了非综合征常染色体显性遗传的人类家系中一系列发育中的主动脉瓣异常和严重的瓣膜钙化。与瓣膜钙化表型一致的是，Notch1转录本在发育中的小鼠主动脉瓣中含量最高，并且Notch1抑制了成骨细胞命运的中央转录调节因子Runx2的活性。毛发相关转录抑制因子家族(HRT)被Notch1信号激活，与Runx2相互作用，并抑制Runx2的转录活性，而不依赖于组蛋白脱乙酰酶的活性。这些结果表明，NOTCH1突变会导致早期的主动脉瓣发育缺陷和后来的钙沉积抑制，从而导致进行性主动脉瓣疾病。
Calcification of the aortic valve is the third leading cause of heart disease in adults(1). The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1 - 2% of the population(2). Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.