Contributions of sex chromosomal gene homologues to X monosomy

Turner综合征(TS)是由45，X核型(XO)引起的，XO是人类最常见的非整倍体 子宫(1.5%)和最常见的自然流产原因(~15%)。除了这一点， 主要的产前负担，TS患者(2000年活产儿中有1人)患有矮小和认知障碍， 肾脏和严重的心血管缺陷。后者跨越先天性心脏病和主动脉瓣不全。 发展，这使致命的主动脉事件的风险比一般情况下增加了近两个数量级 人口。总体而言，仅心血管畸形一项就会使TS队列中的预期寿命缩短超过1 十年。 了解TS的确切发育遗传学病因是更好地预测和 有可能解决这样的不利后果。然而，TS相关的心脏和主动脉缺如，也不是 到目前为止，X单体的高终止率已被定位于特定的基因。我们的中心假设是 TS是由于编码在两性身上的同源基因子集单倍性不足造成的 染色体。这项应用的目的是量化第二性别对基因剂量的影响。 人诱导多能干细胞上的染色体(Y或非活性X)及分化平滑 肌肉细胞(SMC)，并缩小与SMC发育相关的X-Y基因对的子集。 功能。我们已经从存在嵌合体的个体中建立了其他相同基因的HiPSCs 第二条性染色体。我们将比较HiPSC和SMC基因的表达和分化 潜力，同时排除遗传变异的影响，并利用诱导节段性和基因特异性 分析X-Y基因对的作用。这些HiPSC和衍生的SMC面板将使我们能够 确定对第二性别的存在和身份敏感的细胞特征、基因和途径 染色体，并有助于揭示它们对X单体和特纳综合征的可能影响。 。

Turner syndrome (TS) results from 45,X karyotype (XO), which is both the most common aneuploidy in utero (1.5%) and the single most frequent cause (~15%) of spontaneous termination. In addition to this dominant prenatal burden, TS individuals (1 in 2000 live births) suffer from short stature as well as cognitive, renal and serious cardiovascular defects. The latter span congenital heart defects and improper aortic development, which elevate the risk of fatal aortic events by almost two orders of magnitude over the general population. Collectively, cardiovascular malformations alone shorten life expectancy in the TS cohort by over a decade. Understanding the exact developmental-genetic etiology of TS is fundamental to better predicting and possibly addressing such adverse outcomes. However, neither TS-associated heart and aortic defects, nor the high termination rate of X monosomy have been mapped to specific genes to-date. Our central hypothesis is that TS results from a haploinsufficiency in a subset of homologous genes that are encoded on both sex chromosomes. The objectives of this application are to quantify the gene dosage impact of the second sex chromosome (Y or inactive X) on human induced pluripotent stem cells (hiPSCs) and differentiated smooth muscle cells (SMCs), and to narrow in on a subset of X-Y gene pairs relevant to SMC development and function. We have established otherwise isogenic hiPSCs from individuals that were mosaic for the presence of the second sex chromosome. We will compare hiPSC and SMC gene expression and differentiation potential while excluding the impact of genetic variation, and utilize both induced segmental and gene-specific deletions to dissect contributions of X-Y gene pairs. These hiPSC and derived SMC panels will enable us to identify cellular traits, genes and pathways sensitive to the presence and identity of the second sex chromosome, and help to uncover their possible impact on X monosomy and Turner syndrome. .