The Common P450 Oxidoreductase Variant A503V Is Not a Modifier Gene for 21-Hydroxylase Deficiency

Gomes, Larissa; Huang, Ningwu; Agrawal, Vishal; Mendonça, Berenice Bilharinho; Bachega, Tânia A. S. S.; Miller, Walter L.

doi:10.1210/jc.2008-0304

Cited by 48 publications

(31 citation statements)

References 20 publications

(39 reference statements)

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“…8,28 By contrast, A503V had 80% of WT activity to support the 21-hydroxylation of progesterone by human P450c21, and 95% of WT ability to support the 21-hydroxylation of 17-OH-progesterone. 29 Thus, although A503V is evidently not a modifier gene, since it only moderately impaired the metabolism of testosterone, 15,30 it could be assigned a synergistic role 12 in causing disease.…”

Section: Discussionmentioning

confidence: 99%

Delayed diagnosis of disorder of sex development (DSD) due to P450 oxidoreductase (POR) deficiency

Koika¹,

Armeni²,

Georgopoulos³

2016

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CAse PReseNTATION: A 36-year old man, operated on for cryptorchidism at the age of 8 years, was referred to the Outpatient Clinic of Reproductive endocrinology for investigation of infertility. Clinical examination revealed ambiguous genitalia: penis 4-5 cm, testicular volume 2-3 ml, hypospadias, hypertrophic foreskin and scrotum bifida. Mild hypertension was confirmed. No skeletal malformations were detected. DesIgN: hormonal and electrolytic determinations as well as semen analysis were conducted. PCR of the coding regions of 17-hydroxylase/17,20 lyase (P450c17) and of P450 oxidoreductase (POR) genes was also performed. ResULTs: Normal levels of electrolytes, low levels of androgens, high levels of gonadotropins and 17-hydroxyprogesterone as well as azoospermia were detected. Karyotype was shown to be 46,xy. Both hCg and ACTh stimulation significantly increased 17-hydroxyprogesterone with no increase in androgens. The diagnosis was congenital adrenal hyperplasia with apparent combined P450c17 and P450c21 deficiency due to mutations in the POR gene. sequencing of the POR gene revealed: one deletion in exon 12 (Del 1696_1698delgTC >del531valine) and one missense mutation in exon 7 (A259g) as well as two polymorphisms: rs1057868 (C/T A503v) and rs1057870 (g/A s572s) in exons 12 and 13, respectively. No nucleotide changes were detected in the 8 exons of P450c17. CONCLUsIONs: Molecular findings were consistent with the diagnosis of P450 oxidoreductase deficiency. Despite this severe deficiency, skeletal malformations simulating Antley-Bixler syndrome, which usually characterize the most severe forms, were not confirmed. This discrepancy could be attributed to the differential impact of a POR variant on each one of the P450 enzymes.

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Section: Discussionmentioning

confidence: 99%

Delayed diagnosis of disorder of sex development (DSD) due to P450 oxidoreductase (POR) deficiency

Koika¹,

Armeni²,

Georgopoulos³

2016

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“…The common POR coding region polymorphism A503V, with an allele frequency of 19 to 36%, causes 30 to 40% reduction in POR activity (Huang et al, 2005. However, the impact of A503V on P450 activity has been found to be variable, depending on the P450 enzyme involved and the substrate studied Gomes et al, 2008Gomes et al, , 2009Miller et al, 2009Miller et al, , 2011Oneda et al, 2009;Sandee et al, 2010). The ability of this variant to support P450-mediated warfarin metabolism has not been examined in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…At present, more than 800 POR SNPs (Hart et al, 2008;Gomes et al, 2008; NCBI dbSNP database, http:// www.ncbi.nlm.nih.gov/snp) and 41 POR alleles (Sim et al, 2009; http://www.cypalleles.ki.se/por.htm) have been identified. Rare POR coding region mutations, identified in patients with Antley-Bixler syndrome and congenital adrenal hyperplasia, cause dramatic decreases in POR activity and the activities of microsomal steroidogenic P450 enzymes Flück et al, 2004;Huang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Identification of Cytochrome P450 Oxidoreductase Gene Variants That Are Significantly Associated with the Interindividual Variations in Warfarin Maintenance Dose

Zhang¹,

Li²,

Ding³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Cytochrome P450 oxidoreductase (POR) is required for drug metabolism by all microsomal cytochrome P450 enzymes. The aim of this study was to investigate whether any of the common single nucleotide polymorphisms (SNPs) in the POR gene and its flanking intergenic sequences correlate with interindividual variations in the warfarin maintenance dose (which is determined partly by rates of warfarin metabolism) in patients undergoing anticoagulation therapy. Warfarin dose and patients' demographic and clinical information were collected from 124 patients, who had attained a stable warfarin dose while receiving treatment at the Stratton VA Medical Center. Genomic DNAs were isolated from blood samples and were genotyped for 15 SNPs (including 10 SNPs on the POR gene). Association analysis was performed on 122 male patients by linear regression. Simple regression analysis revealed that vitamin K epoxide reductase complex subunit 1 (VKORC1) ؊1639A>G, CYP2C9*2, CYP2C9*3, age, and chronic aspirin therapy were significantly associated with warfarin dose. In contrast, multiple regression analysis revealed that, in addition to several known factors contributing to the variations in warfarin maintenance dose (VKORC1 ؊1639A>G, CYP2C9*2, CYP2C9*3, CYP4F2 rs2108622, and chronic aspirin therapy), three common POR SNPs (؊173C>A, ؊208C>T, and rs2868177) were also significantly associated with variations in warfarin maintenance dose. These results indicate, for the first time, that three common SNPs in the POR gene may contribute to the interindividual variability in warfarin maintenance dose. Further studies on functional characterization of the POR SNPs identified, including their impact on the in vivo metabolism of additional drugs, are needed.

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“…Moreover, different receptor numbers or binding affinity for androgens, cortisol or aldo sterone may contribute to the phenotypic variability. Also, the activity of transcription factors and the expression of transport proteins may be individually regulated [34].…”

Section: Resultsmentioning

confidence: 99%

Intron 2 Splice Mutation at CYP21 Gene in Patients with Congenital Adrenal Hyperplasia in the Republic of Macedonia

Anastasovska¹,

Kočova²

2010

Balkan Journal of Medical Genetics

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Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder. In 90-95% of cases it results from mutations in the gene for 21-hydroxylase (CYP21, also termed CYP21A2 and P450c21). The IVS-II-656 (C/A>G) mutation leaves ~2.0% enzyme activity, and comprises 25% of the classic CYP21 deficiency alleles and 51% of alleles in the salt-wasting form.We performed direct molecular diagnosis of the IVS-II mutation in 41 Macedonian patients with different clinical forms of CAH and 55 of their healthy parents and siblings from 37 unrelated families, using the differential polymerase chain reaction/amplification created restriction site method (PCR/ACRS). The IVS-II mutation was detected in 41.5% patients (29.3% were homozygotes and 12.2% were heterozygotes). All homozygotes had a severe classical CAH phenotype (of which 91.7% were salt-wasting and 8.3% were simple virilizing). Three of the heterozygotes had a salt-wasting (SW) phenotype and were compound heterozygotes. The IVS-II mutation was also found in 30.9% of the family members (18.2% were homozygous and 12.7% were heterozygous) and none had any clinical manifestation. The frequency of the IVS-II mutation (41.5%) in these subjects was similar to that reported elsewhere.

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The Common P450 Oxidoreductase Variant A503V Is Not a Modifier Gene for 21-Hydroxylase Deficiency

Cited by 48 publications

References 20 publications

Delayed diagnosis of disorder of sex development (DSD) due to P450 oxidoreductase (POR) deficiency

Delayed diagnosis of disorder of sex development (DSD) due to P450 oxidoreductase (POR) deficiency

Identification of Cytochrome P450 Oxidoreductase Gene Variants That Are Significantly Associated with the Interindividual Variations in Warfarin Maintenance Dose

Intron 2 Splice Mutation at CYP21 Gene in Patients with Congenital Adrenal Hyperplasia in the Republic of Macedonia

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