A Novel Homozygous Mutation Causes Ovarian Dysgenesis and Primary Amenorrhea

Overview

Journal J Endocr Soc

Date 2025 Jan 24

PMID 39850788

Authors

Amitay Cohen

Raffaella Rossetti

Natan Florsheim

Abraham O Samson

Paul Renbaum

Erika Carbone

Luca Persani

Ephrat Levy-Lahad

Abdulsalam Abu-Libdeh

David Zangen

Affiliations

Soon will be listed here.

Abstract

Context: Despite a growing number of studies, the genetic etiology in many cases of ovarian dysgenesis is incompletely understood.

Objectives: This work aimed to study the genetic etiology causing absence of spontaneous pubertal development, hypergonadotropic hypogonadism, and primary amenorrhea in 2 sisters.

Methods: Whole-exome sequencing was performed on DNA extracted from peripheral lymphocytes of 2 Palestinian sisters born to consanguineous parents. Following a variant identification, confirming genetic segregation studies were performed in family members. Three-dimensional (3D) modeling for BMP15 dimer and BMP15-GDF-9 heterodimer were followed by functional studies in human ovarian COV434 granulosa cells cotransfected with plasmid harboring either the variant or a wild-type (WT) control, and a second plasmid harboring a luciferase-reporter-gene with a BMP-responsive element.

Results: A novel homozygous c.G959A/p.C320Y mutation was identified in both sisters, and segregated with the disease in the family. By 3D-structure modeling, the mutations were predicted to damage a cysteine-knot motif, disrupt BMP15 dimerization, and severely impair activation of the BMP pathway. The homologous mutation C53Y occurring and identified spontaneously in sheep results in sterility in homozygotes, mimicking the human phenotype here. A 3.8-fold decrease in BMP15 signaling was observed in vitro in cells expressing the homozygous BMP15 mutant when compared to the WT control.

Conclusion: The novel homozygous missense C320Y mutation is the first homozygous human variant causing impaired signaling ability, which correlates with the predicted 3D-structural changes leading to ovarian dysgenesis. The homologous mutation in sheep mimics the human phenotype by infertility. Beyond genetic counseling, and considering ovarian preservation, the ovine model enables further elucidation and interventions in the BMP signaling.

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