Genetic Mechanisms in Klinefelter Syndrome-Related Behaviors

描述（由申请人提供）：Klinefelter综合征（KS）是一种常见的染色体异常，男性有两条X染色体XXY，而不是一条X染色体XY。XXY男性会经历各种先天性发育问题，包括不孕症、雄激素水平降低、肥胖和代谢疾病风险增加、自身免疫性疾病风险增加，以及执行功能改变和语言发育迟缓等认知特征。该项目的长期目标是利用新型小鼠模型鉴定导致Klinefelter综合征行为特征的X染色体基因。一个首要的问题是将导致Klinefelter综合征特征的X染色体基因的直接影响与XXY个体中睾丸激素水平较低引起的直接影响分开。一种新的小鼠模型产生了具有睾丸或卵巢的XXY、XY和XX小鼠，因此可以识别不需要睾丸分泌物的性染色体效应，或者当睾丸分泌物不能解释差异时发生的性染色体效应。小鼠将在一系列与Klinefelter综合征相关的行为测量中进行比较，以评估执行功能，发声发展和伴侣偏好。6个特定的X染色体基因的表达水平是导致Klinefelter综合征的主要候选基因，将被直接操纵以评估小鼠模型中哪些是/可能是致病基因。

DESCRIPTION (provided by applicant): Klinefelter Syndrome (KS) is a common chromosomal abnormality of males who have two X chromosomes XXY, rather than one, XY. XXY males experience a variety of congenital developmental problems, including infertility, lower levels of androgens, increased risk for obesity and metabolic disease, increased risk for autoimmune diseases, and cognitive features including alterations in executive function and delayed language development. The long-term objectives of this project are to identify X chromosome genes that cause behavioral features of Klinefelter Syndrome, using novel mouse models. An overarching question is to separate the direct effects of X chromosome genes that cause Klinefelter Syndrome traits, from those caused by lower testosterone levels in XXY individuals. A novel mouse model produces XXY, XY, and XX mice that have either testes or ovaries, so that sex chromosomal effects can be identified that do not require testicular secretions, or occur when testicular secretions do not explain differences. Mice will be compared in a series of Klinefelter Syndrome-relevant behavioral measurements that assess executive functions, development of vocalizations, and partner preference. The expression levels of six specific X chromosome genes, which are the major candidates for causing the features of Klinefelter Syndrome, will be directly manipulated to assess which is/are likely the causal genes in the mouse model.