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. .

Public Health Relevance

Although females have two X chromosomes, only one X is active in any given cell, while the other is inactive. However, some X-linked genes are expressed from both X chromosomes and thought to be lacking in dosage in Turner Syndrome (TS). This chromosomal abnormality (45,X or XO) is observed in 1:2000 live births, and causes high rates of serious heart defects in TS patients. The exact identity and relative contributions of X-linked genes to TS is unknown. The research program described herein aims to answer these questions in cell cultures models relevant to cardiovascular defects and inform research into TS and other X-linked diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Kaltman, Jonathan R
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University of Connecticut
Schools of Medicine
United States
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