Novel CYP19A1 Mutations Extend the Genotype-Phenotype Correlation and Reveal the Impact on Ovarian Function.
- Praveen VP Department of Endocrinology, Amrita Institute of Medical Sciences, Kochi, Kerala, India.
- Ladjouze A Department of Pediatrics, CHU Bab El Oued, Algiers, Algeria.
- Sauter KS Department of Pediatrics, Division of Pediatric Endocrinology, Diabetology and Metabolism University Children's Hospital Bern, Switzerland, and Department of Biomedical Research, University of Bern, Bern, Switzerland.
- Pulickal A Department of Endocrinology, Amrita Institute of Medical Sciences, Kochi, Kerala, India.
- Katharopoulos E Department of Pediatrics, Division of Pediatric Endocrinology, Diabetology and Metabolism University Children's Hospital Bern, Switzerland, and Department of Biomedical Research, University of Bern, Bern, Switzerland.
- Trippel M Institute of Pathology, University of Bern, Bern, Switzerland.
- Perren A Institute of Pathology, University of Bern, Bern, Switzerland.
- Pandey AV Department of Pediatrics, Division of Pediatric Endocrinology, Diabetology and Metabolism University Children's Hospital Bern, Switzerland, and Department of Biomedical Research, University of Bern, Bern, Switzerland.
- Flück CE Department of Pediatrics, Division of Pediatric Endocrinology, Diabetology and Metabolism University Children's Hospital Bern, Switzerland, and Department of Biomedical Research, University of Bern, Bern, Switzerland.
- 2020-04-23
Published in:
- Journal of the Endocrine Society. - 2020
CYP19A1
aromatase deficiency
disorder of sexual development
estrogen synthesis
hyperandrogenism
virilization
English
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.
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1210/jendso/bvaa030
- PMID 32318648
- Persistent URL
- https://folia.unifr.ch/global/documents/263902
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