Molecular Pharmacology Laboratory (FARMOL), Faculty of Health Sciences, University of Brasilia, Brasilia-DF, Brazil.
Section of Endocrinology, Gonadal and Adrenal Diseases Clinics, University Hospital of Brasilia, Brasilia-DF, Brazil.
J Clin Invest. 2023 Dec 1;133(23):e161701. doi: 10.1172/JCI161701.
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.
三姐妹均由近亲父母所生，表现出一种独特的 Müllerian 异常，其特征为子宫发育不全，伴有薄型雌激素无反应性子宫内膜和原发性闭经，但存在自发性输卵管妊娠。通过全外显子组测序和全面的遗传分析，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，以及产前和产后 Osr1/Osr1 在小鼠发育中的 Müllerian 管（MDs）和子宫内膜中的表达模式。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。人类子宫 OSR1/OSR1 表达主要在子宫内膜中。小鼠 Osr1 在 E13.5 胚胎的 MDs 和 Wolffian 管（WDs）中表达，从颅侧向尾侧。E13.5 Osr1-/- 胚胎的左侧没有 MDs，右侧 MDs 被截断在颅侧。产后，Osr1 在小鼠子宫中表达贯穿其整个生命周期，在出生后第 14 天和第 28 天达到峰值。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 MD 发育和子宫内膜容受性很重要，可能与子宫因素不孕有关。
