POR Polymorphisms Are Associated with 21 Hydroxylase Deficiency

Overview

Journal J Endocrinol Invest

Publisher Springer

Specialty Endocrinology

Date 2021 Mar 5

PMID 33666875

Citations 3

Authors

F Pecori Giraldi

S Einaudi

A Sesta

F Verna

M Messina

C Manieri

E Menegatti

L Ghizzoni

Affiliations

Soon will be listed here.

Abstract

Purpose: Genotype-phenotype correlation in congenital 21 hydroxylase deficiency is strong but by no means absolute. Indeed, clinical and hormonal features may vary among patients carrying similar CYP21A2 mutations, suggesting that modifier genes may contribute to the phenotype. Aim of the present study was to evaluate whether polymorphisms in the p450 oxidoreductase (POR) gene may affect clinical features in patients with 21 hydroxylase deficiency METHODS: Sequencing of the POR gene was performed in 96 patients with 21 hydroxylase deficiency (49 classic, 47 non-classic) and 43 control subjects.

Results: Prevalence of POR polymorphisms in patients with 21 hydroxylase was comparable to controls and known databases. The rs2228104 polymorphism was more frequently associated with non-classic vs classic 21 hydroxylase deficiency (allelic risk 7.09; 95% C.I. 1.4-29.5, p < 0.05). Classic 21 hydroxylase-deficient carriers of the minor allele in the rs2286822/rs2286823 haplotype presented more frequently the salt-wasting form (allelic risk 1.375; 95% C.I. 1.138-1.137), more severe Prader stage at birth (allelic risk 3.85; 95% C.I. 3.78-3.92), higher ACTH levels, and younger age at diagnosis.

Conclusions: Polymorphisms in the POR gene are associated with clinical features of 21 hydroxylase deficiency both as regards predisposition to classic vs non-classic forms and severity of classic adrenal hyperplasia.

Citing Articles

Genetic Testing for a Patient with Suspected 3 Beta-Hydroxysteroid Dehydrogenase Deficiency: A Case of Unreported Genetic Variants.

Menegatti E, Tessaris D, Barinotti A, Matarazzo P, Einaudi S J Clin Med. 2022; 11(19).

PMID: 36233635 PMC: 9573289. DOI: 10.3390/jcm11195767.

Congenital adrenal hyperplasia, disorders of sex development, and infertility in patients with POR gene pathogenic variants: a systematic review of the literature.

Gusmano C, Cannarella R, Crafa A, Barbagallo F, La Vignera S, Condorelli R J Endocrinol Invest. 2022; 46(1):1-14.

PMID: 35842891 PMC: 9829634. DOI: 10.1007/s40618-022-01849-9.

The broad phenotypic spectrum of 17α-hydroxylase/17,20-lyase (CYP17A1) deficiency: a case series.

Sun M, Mueller J, Gilligan L, Taylor A, Shaheen F, Noczynska A Eur J Endocrinol. 2021; 185(5):729-741.

PMID: 34524979 PMC: 8558848. DOI: 10.1530/EJE-21-0152.

References

Ng P, Henikoff S . SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003; 31(13):3812-4. PMC: 168916. DOI: 10.1093/nar/gkg509. View

Napolitano E, Manieri C, Restivo F, Composto E, Lanfranco F, Repici M . Correlation between genotype and hormonal levels in heterozygous mutation carriers and non-carriers of 21-hydroxylase deficiency. J Endocrinol Invest. 2010; 34(7):498-501. DOI: 10.3275/7225. View

Arkwright P, Laurie S, Super M, Pravica V, Schwarz M, Webb A . TGF-beta(1) genotype and accelerated decline in lung function of patients with cystic fibrosis. Thorax. 2000; 55(6):459-62. PMC: 1745768. DOI: 10.1136/thorax.55.6.459. View

Arlt W, Walker E, Draper N, Ivison H, Ride J, Hammer F . Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet. 2004; 363(9427):2128-35. DOI: 10.1016/S0140-6736(04)16503-3. View

Zhang H, Li Z, Liu J, Liu T, Wang P, Fang Y . Correlation of Cytochrome P450 Oxidoreductase Expression with the Expression of 10 Isoforms of Cytochrome P450 in Human Liver. Drug Metab Dispos. 2016; 44(8):1193-200. PMC: 4986620. DOI: 10.1124/dmd.116.069849. View

Xiao X, Ma G, Li S, Wang M, Liu N, Ma L . Functional POR A503V is associated with the risk of bladder cancer in a Chinese population. Sci Rep. 2015; 5:11751. PMC: 4485255. DOI: 10.1038/srep11751. View

Pecori Giraldi F, Saccani A, Cavagnini F . Assessment of ACTH assay variability: a multicenter study. Eur J Endocrinol. 2011; 164(4):505-12. DOI: 10.1530/EJE-10-0962. View

Pandey A, Sproll P . Pharmacogenomics of human P450 oxidoreductase. Front Pharmacol. 2014; 5:103. PMC: 4023047. DOI: 10.3389/fphar.2014.00103. View

Fang Y, Gao N, Tian X, Zhou J, Zhang H, Gao J . Effect of P450 Oxidoreductase Polymorphisms on the Metabolic Activities of Ten Cytochrome P450s Varied by Polymorphic CYP Genotypes in Human Liver Microsomes. Cell Physiol Biochem. 2018; 47(4):1604-1616. DOI: 10.1159/000490934. View

10.

Einaudi S, Napolitano E, Restivo F, Motta G, Baldi M, Tuli G . Genotype, phenotype and hormonal levels correlation in non-classical congenital adrenal hyperplasia. J Endocrinol Invest. 2010; 34(9):660-4. DOI: 10.3275/7410. View

11.

New M, Abraham M, Gonzalez B, Dumic M, Razzaghy-Azar M, Chitayat D . Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 2013; 110(7):2611-6. PMC: 3574953. DOI: 10.1073/pnas.1300057110. View

12.

Miller W, Huang N, Agrawal V, Giacomini K . Genetic variation in human P450 oxidoreductase. Mol Cell Endocrinol. 2008; 300(1-2):180-4. DOI: 10.1016/j.mce.2008.09.017. View

13.

Chemaitilly W, Betensky B, Marshall I, Wei J, Wilson R, New M . The natural history and genotype-phenotype nonconcordance of HLA identical siblings with the same mutations of the 21-hydroxylase gene. J Pediatr Endocrinol Metab. 2005; 18(2):143-53. DOI: 10.1515/jpem.2005.18.2.143. View

14.

Elens L, Sombogaard F, Hesselink D, van Schaik R, van Gelder T . Single-nucleotide polymorphisms in P450 oxidoreductase and peroxisome proliferator-activated receptor-α are associated with the development of new-onset diabetes after transplantation in kidney transplant recipients treated with tacrolimus. Pharmacogenet Genomics. 2013; 23(12):649-57. DOI: 10.1097/FPC.0000000000000001. View

15.

Tomkova M, Panda S, Seda O, Baxova A, Hulkova M, Masters B . Genetic variations in NADPH-CYP450 oxidoreductase in a Czech Slavic cohort. Pharmacogenomics. 2015; 16(3):205-15. PMC: 4662547. DOI: 10.2217/pgs.14.169. View

16.

Ghizzoni L, Cappa M, Vottero A, Ubertini G, Carta D, Di Iorgi N . Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche. Eur J Endocrinol. 2011; 165(2):307-14. DOI: 10.1530/EJE-11-0119. View

17.

Simonetti L, Bruque C, Fernandez C, Benavides-Mori B, Delea M, Kolomenski J . CYP21A2 mutation update: Comprehensive analysis of databases and published genetic variants. Hum Mutat. 2017; 39(1):5-22. DOI: 10.1002/humu.23351. View

18.

Dhir V, Ivison H, Krone N, Shackleton C, Doherty A, Stewart P . Differential inhibition of CYP17A1 and CYP21A2 activities by the P450 oxidoreductase mutant A287P. Mol Endocrinol. 2007; 21(8):1958-68. DOI: 10.1210/me.2007-0066. View

19.

Huang K, Liao X, Han C, Wang X, Yu T, Yang C . Genetic variants and Expression of Cytochrome p450 Oxidoreductase Predict Postoperative Survival in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma. J Cancer. 2019; 10(6):1453-1465. PMC: 6485213. DOI: 10.7150/jca.28919. View

20.

Speiser P, Azziz R, Baskin L, Ghizzoni L, Hensle T, Merke D . Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010; 95(9):4133-60. PMC: 2936060. DOI: 10.1210/jc.2009-2631. View