Contributions of sex chromosomal gene homologues to X monosomy

性染色体基因同源物对 X 单体的贡献

• 批准号: 9912836
• 负责人: Stefan F. Pinter
• 金额: $ 39.88万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912836
• 关键词: Address; Aneuploidy; Aorta; Blood Vessels; Cardiovascular system; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell Lineage; Cells; Chromosome abnormality; Clone Cells; Cognitive; Complement; Complex; Congenital Heart Defects; Defect; Deposition; Development; Disease; Embryonic Development; Engineering; Epigenetic Process; Etiology; Event; Extracellular Matrix; FBN1; Female; Fibroblasts; Functional disorder; Gene Dosage; Gene Expression; General Population; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Genotype; Goals; Heart; Heart Abnormalities; Homologous Gene; Hormonal; Human; Human Genetics; Impairment; In Vitro; Individual; Karyotype; Kidney; Knowledge; Left; Life Expectancy; Link; Live Birth; Maps; Marfan Syndrome; Measures; Mediating; Mesoderm; Methods; Modeling; Mosaicism; Mus; Neural Crest; Pathway interactions; Patients; Phenocopy; Phenotype; Process; Pseudoautosomal Region; Research; Risk; Series; Sex Chromosomes; Side; Site; Smooth Muscle Myocytes; Tunica Media; Turner' s Syndrome; Vascular Smooth Muscle; X Chromosome; X Inactivation; Y Chromosome; adverse outcome; ascending aorta; cohort; developmental genetics; differential expression; dosage; genetic architecture; genotypic sex; imprint; in utero; induced pluripotent stem cell; male; malformation; parity; prenatal; programs; recombinase; sex; stem cell biology; stem cell differentiation; stem cell model; tool; trait; transcriptome; transcriptome sequencing

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. .

Turner综合征（TS）由45，X染色体核型（XO）引起，这是最常见的非整倍体， 子宫（1.5%）和自发终止的单一最常见原因（~15%）。除此之外 占主导地位的产前负担，TS个体（1/2000活产）患有身材矮小以及认知， 肾脏和严重的心血管缺陷。后者跨越先天性心脏缺陷和不适当的主动脉 发展，这将致命性主动脉事件的风险提高了近两个数量级，超过了一般的 人口总的来说，在TS队列中，仅心血管畸形就将预期寿命缩短了10%以上。 十年 了解TS的确切发育遗传病因是更好地预测和治疗TS的基础。 可能解决这种不利的结果。然而，无论是TS相关的心脏和主动脉缺陷， 迄今为止，X单体性高终止率已定位于特定基因。我们的核心假设是 TS是由两性同源基因的一个子集的单倍不足引起的， 染色体本申请的目的是量化第二性别的基因剂量影响 在人诱导多能干细胞（hiPSC）上的染色体（Y或失活X）和分化的光滑 肌肉细胞（SMC），并缩小在一个子集的X-Y基因对有关SMC的发展和 功能我们已经从个体中建立了其他方面的同基因hiPSC，这些个体因存在 第二性染色体的基因我们将比较hiPSC和SMC的基因表达和分化 潜力，同时排除遗传变异的影响，并利用诱导的节段性和基因特异性 删除以剖析X-Y基因对的贡献。这些hiPSC和衍生SMC面板将使我们能够 识别对第二性的存在和身份敏感的细胞特征、基因和途径 染色体，并帮助揭示其对X单体和特纳综合征的可能影响。 .