Three sisters, born from consanguineous parents, manifested a unique Müllerian anomaly characterized by uterine hypoplasia with thin estrogen-unresponsive endometrium and primary amenorrhea, but with spontaneous tubal pregnancies. Through whole-exome sequencing followed by comprehensive genetic analysis, a missense variant was identified in the OSR1 gene. We therefore investigated OSR1/OSR1 expression in postpubertal human uteri, and the prenatal and postnatal expression pattern of Osr1/Osr1 in murine developing Müllerian ducts (MDs) and endometrium, respectively. We then investigated whether Osr1 deletion would affect MD development, using WT and genetically engineered mice. Human uterine OSR1/OSR1 expression was found primarily in the endometrium. Mouse Osr1 was expressed prenatally in MDs and Wolffian ducts (WDs), from rostral to caudal segments, in E13.5 embryos. MDs and WDs were absent on the left side and MDs were rostrally truncated on the right side of E13.5 Osr1^–/– embryos. Postnatally, Osr1 was expressed in mouse uteri throughout their lifespan, peaking at postnatal days 14 and 28. Osr1 protein was present primarily in uterine luminal and glandular epithelial cells and in the epithelial cells of mouse oviducts. Through this translational approach, we demonstrated that OSR1 in humans and mice is important for MD development and endometrial receptivity and may be implicated in uterine factor infertility.

中文翻译：

---

OSR1 破坏通过受损的苗勒氏管发育和子宫内膜容受性导致子宫因素不孕

近亲父母所生的三姐妹表现出独特的苗勒氏管异常，其特征是子宫发育不全、子宫内膜薄、对雌激素无反应和原发性闭经，但有自发性输卵管妊娠。通过全外显子组测序和综合遗传分析，在OSR1基因中发现了一个错义变异。因此，我们研究了青春期后人类子宫中的OSR1 /OSR1 表达，以及小鼠发育中的苗勒管 (MD) 和子宫内膜中Osr1/ Osr1的产前和产后表达模式。然后，我们使用 WT 和基因工程小鼠研究了 Osr1 缺失是否会影响 MD 发育。人子宫OSR1 /OSR1 表达主要在子宫内膜中发现。小鼠 Osr1 在 E13.5 胚胎的 MD 和沃尔夫管 (WD) 中（从头端到尾端）产前表达。E13.5 Osr1 ^–/–胚胎的左侧 MD 和 WD 缺失，右侧 MD 被截断。出生后，Osr1在小鼠的整个生命周期中在子宫中表达，在出生后 14 天和 28 天达到高峰。Osr1 蛋白主要存在于子宫腔和腺上皮细胞以及小鼠输卵管的上皮细胞中。通过这种转化方法，我们证明了人类和小鼠中的 OSR1 对于 MD 发育和子宫内膜容受性很重要，并且可能与子宫因素不孕有关。