Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease
Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease
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DOI：
10.1016/j.ajhg.2016.11.008
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发表时间：
2017-01-05
影响因子：
9.8
通讯作者：
Milewicz, Dianna M.
中科院分区：
文献类型：
--
作者：
Guo, Dong-chuan;Duan, Xue-Yan;Milewicz, Dianna M.
纤维肌性发育不良（FMD）是一组异质性的非动脉粥样硬化和非炎症性动脉疾病，主要涉及肾动脉和脑血管动脉。Grange综合征是一种常染色体隐性遗传疾病，其特征是严重的早发性血管疾病，类似于FMD，并指、短指、并指、骨脆性和学习障碍的不同发病率。来自三名患有Grange综合征的受影响兄弟姐妹的DNA的外显子组测序分析鉴定了YY 1AP 1中的复合杂合无义变体，并且随后在其他与Grange综合征无关的前带中鉴定了纯合无义或移码YY 1AP 1变体。YY 1AP 1编码阴阳1（YY 1）相关蛋白1，是YY 1转录因子的激活因子。我们确定YY 1AP 1定位于细胞核，是INO 80染色质重塑复合物的组成部分，负责转录调控，DNA修复和复制。分子研究表明，血管平滑肌细胞中YY 1AP 1的缺失导致细胞周期停滞，增殖减少，细胞周期调节因子p21/WAF/CDKN 1A水平升高，并破坏TGF-β驱动的平滑肌细胞分化。YY 1AP 1突变作为FMD的原因的鉴定表明，这种情况可能是由潜在的遗传变异导致的，这些变异显著改变了血管平滑肌细胞的表型。
Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated pro bands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-beta-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.