Novel CYP19A1 Mutations Extend the Genotype-Phenotype Correlation and Reveal the Impact on Ovarian Function

Abstract

Context The steroidogenic enzyme aromatase (CYP19A1) is required for estrogen biosynthesis from androgen precursors in the ovary and extragonadal tissues. The role of aromatase, and thus estrogens, is best illustrated by genetic variations of the CYP19A1 gene leading to aromatase deficiency or excess. Objective The objective of this work is to characterize novel CYP19A1 variants. Design, setting, and patients Variants causing aromatase deficiency were suspected in four 46,XX children of African and Indian origin by careful clinical phenotyping. Sequencing of the CYP19A1 gene identified novel variants. Minigene experiments, aromatase activity assay, and computational, and histological analysis were used to characterize the variants. Main outcome measure and results CYP19A1 variants were found in all patients: a deletion in intron 9 leading to p.P423_H503del, a delins variant at p.P154, and point variants p.V161D, p.R264C, p.R375C. Except for R264C, all variants showed a loss of function. Protein structure and dynamics studies were in line with functional assays. The 2 female patients with delins variants manifested with ambiguous genitalia at birth. Histologic investigation revealed normal ovarian tissue on one side and a streak gonad on the other. Two female patients presented with abnormal pubertal development and polycystic ovaries. Conclusion In girls, aromatase deficiency usually manifests at birth, but diagnosis may also be made because of abnormal pubertal development or ovarian torsion due to (poly)cystic ovaries. The ovary harboring CYP19A1 variants may present as streak gonad or appears normal at birth, but is then at very high risk to produce cysts with aging and is therefore prone to ovarian torsion.

Fetal estrogens are not involved in sex determination but critical for early ovarian differentiation

“…The results of the present study demonstrate that estrogens play no role on the ovary/testis determinism of the rabbit gonad. A similar finding had already been described in humans, where several cases of total CYP19A1 gene inactivation were reported (Akcurin et al 2016; Zhu et al 2016; Mazen et al 2017; Unal et al 2018; Praveen et al 2020). In spite of numerous symptoms affecting the development of gonads, of external genitalia and of breast in the girl, with multiple disorders in energy and bone metabolisms, there was no sex reversal of the human ovary as regard to the genetic sex (Zhu et al 2016).…”

Disorders of Sex Development: Classification, Review, and Impact on Fertility

“…Therefore, the patient may present with primary amenorrhea (i.e., hypergonadotropic hypogonadism) and mild virilization. Recently, Praveen et al [159] pointed out that although aromatase deficiency generally manifests at birth in females, the diagnosis may also be made later, either by abnormal pubertal development or by ovarian torsion due to (poly)cystic ovaries.…”

Association of the CYP19A1 rs700518 Polymorphism with Selected Markers of Bone Metabolism in Women with Hyperandrogenism

“…It was found that normal aromatase activity is essential for the proper development of ovarian follicles during fetal development, their maturation, and during ovulation in the reproductive period. A deficiency of aromatase in most cases leads to the development of a polycystic ovary phenotype [ 12 ]. The CYP19A1 rs700518 polymorphism is based on the conversion of adenine (A) to guanine (G) and is one of the most widely studied polymorphisms in relation to bone mineral density (BMD) and osteoporosis.…”