OSR1 disruption contributes to uterine factor infertility via impaired Müllerian duct development and endometrial receptivity
Adriana Lofrano-Porto, … , Rulang Jiang, Ursula B. Kaiser
Adriana Lofrano-Porto, … , Rulang Jiang, Ursula B. Kaiser
Published October 17, 2023
Citation Information: J Clin Invest. 2023;133(23):e161701. https://doi.org/10.1172/JCI161701.
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Research Article Development Reproductive biology

OSR1 disruption contributes to uterine factor infertility via impaired Müllerian duct development and endometrial receptivity

Abstract

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.

Authors

Adriana Lofrano-Porto, Sidney Alcântara Pereira, Andrew Dauber, Jordana C.B. Bloom, Audrey N. Fontes, Naomi Asimow, Olívia Laquis de Moraes, Petra Ariadne T. Araujo, Ana Paula Abreu, Michael H. Guo, Silviene F. De Oliveira, Han Liu, Charles Lee, Wendy Kuohung, Michella S. Coelho, Rona S. Carroll, Rulang Jiang, Ursula B. Kaiser

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Figure 2

A missense mutation in the OSR1 gene of a 29-year-old woman (proband) with primary amenorrhea and a developmental anomaly of the reproductive tract.

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A missense mutation in the OSR1 gene of a 29-year-old woman (proband) wi...
(A) Family pedigree; squares indicate male family members, circles female family members. (B) Partial sequencing chromatographs of OSR1 gene. (A and B) The 3 affected sisters are homozygous (black circles (A) and black arrows (B)) for a missense mutation in the OSR1 gene, resulting in a p.V108F substitution. The proband (II.4, red arrow) and her affected sister (II.6) developed spontaneous left tubal pregnancies. Parents (I.1 and I.2) are first-degree cousins and are heterozygous (half-black/half-white square and circle) for the OSR1 p.V108F mutation, as is a fertile brother (II.7). The infertile male sibling (II.3) and the niece (III.3) were not available for clinical and genetic evaluation. Unrelated individuals are represented in gray (not studied). NM denotes nonmutated.