睾丸决定因素
硫氧化物9
增强子
性反转
性发育障碍
生物
遗传学
性腺
基因复制
基因
转录因子
染色质
抄写(语言学)
细胞生物学
基因表达调控
发起人
基因表达
Y染色体
内分泌学
作者
Brittany Croft,Thomas Ohnesorg,Jacqueline Hewitt,Josephine Bowles,Alexander Quinn,Jacqueline Tan,Vincent Corbin,Emanuele Pelosi,Jocelyn van den Bergen,Rajini Sreenivasan,Ingrid Knarston,Gorjana Robevska,Dung Vu,John M. Hutson,Vincent R. Harley,Katie Ayers,Peter Koopman,Andrew H. Sinclair
标识
DOI:10.1038/s41467-018-07784-9
摘要
Disorders of sex development (DSDs) are conditions affecting development of the gonads or genitalia. Variants in two key genes, SRY and its target SOX9, are an established cause of 46,XY DSD, but the genetic basis of many DSDs remains unknown. SRY-mediated SOX9 upregulation in the early gonad is crucial for testis development, yet the regulatory elements underlying this have not been identified in humans. Here, we identified four DSD patients with overlapping duplications or deletions upstream of SOX9. Bioinformatic analysis identified three putative enhancers for SOX9 that responded to different combinations of testis-specific regulators. All three enhancers showed synergistic activity and together drive SOX9 in the testis. This is the first study to identify SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY sex reversal, respectively. These enhancers provide a hitherto missing link by which SRY activates SOX9 in humans, and establish SOX9 enhancer mutations as a significant cause of DSD.
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