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

Overview

Journal J Endocr Soc

Specialty Endocrinology

Date 2020 Apr 23

PMID 32318648

Citations 7

Authors

Valiyaparambil Pavithran Praveen

Asmahane Ladjouze

Kay-Sara Sauter

Annie Pulickal

Efstathios Katharopoulos

Mafalda Trippel

Aurel Perren

Amit V Pandey

Christa E Fluck

Affiliations

Soon will be listed here.

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 gene leading to aromatase deficiency or excess.

Objective: The objective of this work is to characterize novel 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 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: 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 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.

Citing Articles

Expression of steroidogenesis pathway genes in cumulus cells from women with diminished ovarian reserve after gonadotropin administration: A case-control study.

Ahmadnia Z, Montazeri F, Dashti S, Sheikhha M, Lotfi M Int J Reprod Biomed. 2024; 22(9):701-708.

PMID: 39618718 PMC: 11602736. DOI: 10.18502/ijrm.v22i9.17474.

Becoming female: Ovarian differentiation from an evolutionary perspective.

Nicol B, Estermann M, Yao H, Mellouk N Front Cell Dev Biol. 2022; 10:944776.

PMID: 36158204 PMC: 9490121. DOI: 10.3389/fcell.2022.944776.

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

Uzar I, Bogacz A, Sowinska-Przepiera E, Piatek K, Przerwa F, Wolek M J Clin Med. 2022; 11(12).

PMID: 35743606 PMC: 9224995. DOI: 10.3390/jcm11123537.

Fetal Estrogens are not Involved in Sex Determination But Critical for Early Ovarian Differentiation in Rabbits.

Jolivet G, Daniel-Carlier N, Harscoet E, Airaud E, Dewaele A, Pierson C Endocrinology. 2021; 163(1).

PMID: 34614143 PMC: 8598387. DOI: 10.1210/endocr/bqab210.

Approach to the Virilizing Girl at Puberty.

Santi M, Graf S, Zeino M, Cools M, Van de Vijver K, Trippel M J Clin Endocrinol Metab. 2020; 106(5):1530-1539.

PMID: 33367768 PMC: 8063244. DOI: 10.1210/clinem/dgaa948.

References

Shozu M, Akasofu K, Harada T, Kubota Y . A new cause of female pseudohermaphroditism: placental aromatase deficiency. J Clin Endocrinol Metab. 1991; 72(3):560-6. DOI: 10.1210/jcem-72-3-560. View

Smith R, Lovell S, Burke D, Montalvao R, Blundell T . Andante: reducing side-chain rotamer search space during comparative modeling using environment-specific substitution probabilities. Bioinformatics. 2007; 23(9):1099-105. DOI: 10.1093/bioinformatics/btm073. View

Simpson E, Mahendroo M, Means G, Kilgore M, Hinshelwood M, Amarneh B . Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev. 1994; 15(3):342-55. DOI: 10.1210/edrv-15-3-342. View

Grumbach M, Auchus R . Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab. 1999; 84(12):4677-94. DOI: 10.1210/jcem.84.12.6290. View

Mittre Herve M, Kottler M, Pura M . Human gene mutations. Gene symbol: CYP19. Disease: Aromatase deficiency. Hum Genet. 2004; 114(2):224. View

Ghosh D, Lo J, Morton D, Valette D, Xi J, Griswold J . Novel aromatase inhibitors by structure-guided design. J Med Chem. 2012; 55(19):8464-76. PMC: 3469775. DOI: 10.1021/jm300930n. View

Dutta S, Mark-Kappeler C, Hoyer P, Pepling M . The steroid hormone environment during primordial follicle formation in perinatal mouse ovaries. Biol Reprod. 2014; 91(3):68. DOI: 10.1095/biolreprod.114.119214. View

Fluck C, Pandey A . Impact on CYP19A1 activity by mutations in NADPH cytochrome P450 oxidoreductase. J Steroid Biochem Mol Biol. 2016; 165(Pt A):64-70. DOI: 10.1016/j.jsbmb.2016.03.031. View

Wang C, Zhou B, Xia G . Mechanisms controlling germline cyst breakdown and primordial follicle formation. Cell Mol Life Sci. 2017; 74(14):2547-2566. PMC: 11107689. DOI: 10.1007/s00018-017-2480-6. View

10.

Dursun F, Ceylaner S . A Novel Homozygous Gene Mutation: Aromatase Deficiency Mimicking Congenital Adrenal Hyperplasia in an Infant without Obvious Maternal Virilisation. J Clin Res Pediatr Endocrinol. 2018; 11(2):196-201. PMC: 6571529. DOI: 10.4274/jcrpe.galenos.2018.2018.0140. View

11.

Grive K, Freiman R . The developmental origins of the mammalian ovarian reserve. Development. 2015; 142(15):2554-63. PMC: 4529035. DOI: 10.1242/dev.125211. View

12.

Parween S, DiNardo G, Baj F, Zhang C, Gilardi G, Pandey A . Differential effects of variations in human P450 oxidoreductase on the aromatase activity of CYP19A1 polymorphisms R264C and R264H. J Steroid Biochem Mol Biol. 2019; 196:105507. DOI: 10.1016/j.jsbmb.2019.105507. View

13.

Chen Z, Wang O, Nie M, Elison K, Zhou D, Li M . Aromatase deficiency in a Chinese adult man caused by novel compound heterozygous CYP19A1 mutations: effects of estrogen replacement therapy on the bone, lipid, liver and glucose metabolism. Mol Cell Endocrinol. 2014; 399:32-42. PMC: 4457386. DOI: 10.1016/j.mce.2014.09.016. View

14.

Bulun S . Clinical review 78: Aromatase deficiency in women and men: would you have predicted the phenotypes?. J Clin Endocrinol Metab. 1996; 81(3):867-71. DOI: 10.1210/jcem.81.3.8772541. View

15.

Topham C, Srinivasan N, Blundell T . Prediction of the stability of protein mutants based on structural environment-dependent amino acid substitution and propensity tables. Protein Eng. 1997; 10(1):7-21. DOI: 10.1093/protein/10.1.7. View

16.

Britt K, Saunders P, McPherson S, Misso M, Simpson E, Findlay J . Estrogen actions on follicle formation and early follicle development. Biol Reprod. 2004; 71(5):1712-23. DOI: 10.1095/biolreprod.104.028175. View

17.

Gagliardi L, Scott H, Feng J, Torpy D . A case of Aromatase deficiency due to a novel CYP19A1 mutation. BMC Endocr Disord. 2014; 14:16. PMC: 3936939. DOI: 10.1186/1472-6823-14-16. View

18.

Ito Y, Fisher C, Conte F, Grumbach M, Simpson E . Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries. Proc Natl Acad Sci U S A. 1993; 90(24):11673-7. PMC: 48046. DOI: 10.1073/pnas.90.24.11673. View

19.

Belgorosky A, Pepe C, Marino R, Guercio G, Saraco N, Vaiani E . Hypothalamic-pituitary-ovarian axis during infancy, early and late prepuberty in an aromatase-deficient girl who is a compound heterocygote for two new point mutations of the CYP19 gene. J Clin Endocrinol Metab. 2003; 88(11):5127-31. DOI: 10.1210/jc.2003-030433. View

20.

Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J . Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med. 1997; 337(2):91-5. DOI: 10.1056/NEJM199707103370204. View