Alternative titles; symbols
HGNC Approved Gene Symbol: POR
SNOMEDCT: 715733000;
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38): 7:75,915,155-75,986,855 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q11.23 | Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis | 201750 | Autosomal recessive | 3 |
| Disordered steroidogenesis due to cytochrome P450 oxidoreductase | 613571 | 3 |
Cytochrome P450 oxidoreductase is a flavoprotein that donates electrons to all microsomal P450 enzymes, including the steroidogenic enzymes P450c17 (CYP17A1; 609300), P450c21 (CYP21A2; 613815), and CYP51A1 (601637) (Miller, 1986).
Shephard et al. (1989) isolated and sequenced cDNA clones that code for rat and human NADPH-dependent cytochrome P450 reductase.
By Southern blot analysis of DNA isolated from a panel of 8 independent human-rodent somatic cell hybrids, Shephard et al. (1989) determined that cytochrome P450 reductase is encoded by a single gene located on 7pter-q22. By in situ hybridization to metaphase chromosomes, they refined the localization to 7q11.2.
Congenital Adrenal Hyperplasia due to Cytochrome P450 Oxidoreductase Deficiency
Apparent combined P450C17 and P450C21 deficiency (see 613571) is a rare variant of congenital adrenal hyperplasia, first reported by Peterson et al. (1985). Affected girls are born with ambiguous genitalia, indicating intrauterine androgen excess. After birth, however, virilization does not progress and amounts of circulating androgens are low or normal. Affected boys are sometimes born undermasculinized. Boys and girls can also present with bone malformations. Findings of biochemical investigations of urinary steroid excretion in affected patients have shown accumulation of steroid metabolites, indicating impaired C17 and C21 hydroxylation, suggesting concurrent partial deficiencies of the 2 steroidogenic enzymes, P450C17 and P450C21. However, sequencing of the genes encoding these enzymes showed no mutations, which accorded with the idea of a defect in a cofactor that interacts with both enzymes.
Arlt et al. (2004) investigated the underlying molecular basis of congenital adrenal hyperplasia with apparent combined P450C17 and P450C21 deficiency in 3 affected children, a brother and sister and a third unrelated patient. All 3 patients were compound heterozygotes for mutations in the POR gene (see 124015.0002 and 124015.0005 and 124015.0003-124015.0007), whereas their parents and an unaffected sib were heterozygotes. One patient (see 124015.0007) had mild bone abnormalities suggesting Antley-Bixler syndrome.
In a 23-year-old 46,XX Brazilian female with normal breast development, primary amenorrhea, and mild arterial hypertension, but no dysmorphic features, Fluck et al. (2004) detected compound heterozygosity for mutations in the POR gene (see 124015.0003).
Antley-Bixler Syndrome with Disordered Steroidogenesis
In 4 unrelated patients with disordered steroidogenesis including 3 children with bony features of Antley-Bixler syndrome, Fluck et al. (2004) found mutations in the POR gene. This was somewhat surprising since the affected individuals lacked apparent disorders of bile acid synthesis or drug metabolism, which also requires P450 enzymes, and knockout of POR is embryonically lethal in mice (Shen et al., 2002; Otto et al., 2003).
Huang et al. (2005) sequenced the POR gene in 32 individuals with Antley-Bixler syndrome and/or hormonal changes that suggested POR deficiency (201750). Fifteen patients carried POR mutations on both alleles; 4 carried mutations on only 1 allele. The 34 affected POR alleles included 10 with ala287-to-pro (124015.0002), all from whites, and 7 with arg457-to-his (R457H; 124015.0005), including 4 Japanese, 1 African, and 2 Caucasians; 17 of the 34 carried 16 'private' mutations, including 9 missense and 7 frameshift mutations. One of the patients with an Antley-Bixler syndrome-like skeletal phenotype and abnormal steroids and genitalia, in whom Huang et al. (2005) identified compound heterozygosity for a frameshift and a missense mutation in the POR gene (see 124015.0015 and 124015.0016, respectively), was the patient in whom Hurley et al. (2004) had previously found a heterozygous missense mutation of unclear significance in the FGFR1 gene (136350.0011). Huang et al. (2005) recreated these 11 missense mutations, plus 10 others found in databases or reported elsewhere, by site-directed mutagenesis and assessed them by 4 assays: assays that were based on cytochrome c, which is not a physiologic substrate for POR, correlated fully with clinical phenotype, but assays that were based on POR's support of catalysis by P450c17 (the enzyme most closely associated with the hormonal phenotype) provided an excellent genotype/phenotype correlation. Huang et al. (2005) concluded that individuals with an ABS phenotype and normal steroidogenesis have FGFR mutations, whereas those with ambiguous genitalia and disordered steroidogenesis should be recognized as having a distinct new disease: POR deficiency. The existence of 2 distinct disorders was first suggested by Reardon et al. (2000).
Fukami et al. (2005) reported molecular and genetic findings in 10 Japanese patients from 8 families with skeletal findings of ABS and abnormal genitalia and/or impaired steroidogenesis. POR mutations were identified in 15 of 16 alleles from the 8 families; the R457H mutation was found in 10 of 16 alleles and was associated with a specific haplotype. Fukami et al. (2005) suggested that the high frequency of R457H in the Japanese is due to a founder effect. Four other mutations were also identified in these patients: a 1-bp insertion (124015.0011), a 24-bp deletion (124015.0012), a missense mutation (Y578C; 124015.0013), and a silent 15A-G transition (G5G; 124015.0014).
Otto et al. (2003) found that deletion of the Cpr gene in mice resulted in death in early to middle gestation. Cpr -/- embryos exhibited multiple abnormalities, including severe inhibition of vasculogenesis and hematopoiesis and defects in brain and limb development. Some of the abnormalities could be attributed to perturbations in retinoic acid homeostasis. Embryos at 9.5 days postcoitum had significantly elevated levels of retinoic acid and reduced levels of retinol. Furthermore, some of the phenotypes could be either reversed or exacerbated by decreasing or increasing maternal retinoic acid exposure, respectively.
In a child with bony features of Antley-Bixler syndrome and disordered steroidogenesis (ABS1; 201750), Fluck et al. (2004) found heterozygosity for a transversion in the POR gene, 1475T-A, leading to the amino acid substitution val492 to glu (V492E). The mutation was inherited from the mother, who was heterozygous; no mutation in the exons or first 50 basepairs of splice donor-acceptor sites on the paternal allele was found.
In a child with bony features of Antley-Bixler syndrome with genital ambiguity and abnormal steroidogenesis (ABS1; 201750), Fluck et al. (2004) found apparent homozygosity for a nucleotide substitution 859G-C in the POR gene leading to an ala287-to-pro (A287P) substitution. This child had been described by Kelley et al. (2002). The mother was heterozygous for the mutation; paternal DNA was not available.
Huang et al. (2005) sequenced the POR gene in 29 individuals with Antley-Bixler syndrome and/or hormonal findings that suggested POR deficiency. Fifteen patients carried POR mutations on both alleles; 4 carried mutations on only 1 allele. The 34 affected POR alleles included 10 with A287P, all in Caucasians.
For discussion of the A287P mutation in the POR gene that was found in compound heterozygous state in a patient with congenital adrenal hyperplasia due to apparent combined deficiency of P450C17 and P450C21 (613571) by Arlt et al. (2004), see 124015.0005.
In a phenotypically normal woman with amenorrhea and disordered steroidogenesis (613571), Fluck et al. (2004) found compound heterozygosity for 2 mutations in the POR gene, 1706G-A and 1822G-T, leading to the amino acid substitutions cys569 to tyr (C569Y) and val608 to phe (V608F; 124015.0004), respectively. Parental DNA was not available.
For discussion of the C569Y mutation in the POR gene that was found in compound heterozygous state in patients with congenital adrenal hyperplasia associated with apparent combined P450C17 and P450C21 deficiency by Arlt et al. (2004), see 124015.0007.
For discussion of the val608-to-phe (V608F) mutation in the POR gene that was found in compound heterozygous state in a patient with amenorrhea and disordered steroidogenesis (613571) by Fluck et al. (2004), see 124015.0003.
In a child with Antley-Bixler syndrome and disordered steroidogenesis (ABS1; 201750), Fluck et al. (2004) found compound heterozygosity for a 1370G-A transition in the POR gene leading to an arg457-to-his (R457H) substitution on the maternal allele, and a 731+1G-A change (124015.0006) in the first base of the splice donor site of intron 6 on the paternal allele. The corresponding minigene construct retained intron 6, leading to a premature stop codon.
In a female (46,XX) offspring of healthy, unrelated parents of Polish descent with congenital adrenal hyperplasia due to apparent combined deficiency of P450C17 and P450C21 (613571), Arlt et al. (2004) described compound heterozygosity for 2 mutations in the POR gene: A287P (124015.0002) and the R457H mutation. (Arlt et al. (2004) numbered these mutations A284P and R454H, respectively, according to the amino acid position in the protein (GenBank P16435).) The girl was born with clubfeet and ambiguous genitalia, including enlargement of the clitoris and partial labial fusion. Virilization did not progress after birth. Follow-up at 13 years of age showed a marfanoid habitus, scoliosis, arachnodactyly, dysplastic ears, and long, slim limbs. Ovarectomy due to rupture of large ovarian cysts was performed at 14 and 16 years of age. In this family, 5 preceding and 2 subsequent pregnancies resulted in early miscarriages. The unaffected father was heterozygous for A287P; the unaffected mother and younger brother were heterozygous for R457H.
Huang et al. (2005) sequenced the POR gene in 29 individuals with a diagnosis of Antley-Bixler syndrome and/or hormonal findings that suggested POR deficiency. Fifteen patients carried POR mutations on both alleles, and 4 carried mutations on only 1 allele. The 34 affected POR alleles included 7 with R457H, in 4 Japanese, 1 African, and 2 white patients.
Fukami et al. (2005) identified the R457H mutation in 10 of 16 alleles from 8 Japanese families with skeletal findings of ABS and abnormal genitalia and/or impaired steroidogenesis. R457H was associated with a specific haplotype; Fukami et al. (2005) suggested that the high frequency of R457H in the Japanese is due to a founder effect.
Adachi et al. (2006) performed SNP analysis in 5 previously reported patients with POR deficiency and the R457H mutation (4 Japanese and 1 Polish), and found that the non-Japanese patient had the same SNP pattern as Japanese patients, suggesting that R457H is a global founder mutation.
For discussion of the splice site mutation in the POR gene (731+1G-A) that was found in compound heterozygous state in a patient with Antley-Bixler syndrome and disordered steroidogenesis (ABS1; 201750) by Fluck et al. (2004), see 124015.0005.
In a brother and sister with congenital adrenal hyperplasia associated with apparent combined P450C17 and P450C21 deficiency (613571), Arlt et al. (2004) found compound heterozygosity for 2 mutations in the POR gene: a 531T-G transversion in exon 5, resulting in a tyr181-to-asp (Y181D) substitution, and a 1696G-A transition in exon 13, resulting in a cys569-to-tyr (C569Y; 124015.0003). (Arlt et al. (2004) numbered these mutations Y178D and C566Y, respectively, according to the amino acid position in the protein (GenBank P16435).) The girl was born with ambiguous genitalia; ultrasound examination showed the presence of a uterus and ovaries, and the karyotype was confirmed as 46,XX. In addition, she had a broad nasal bridge and ulnar deviation of the wrists with brachytelephalangia and flattened metacarpal epiphyses, features resembling those of Antley-Bixler syndrome (see 207410). Virilization did not progress after birth. In the case of the younger brother, the mother's urinary steroid excretion was monitored longitudinally during pregnancy. Her estriol concentration failed to rise, and androsterone excretion rose, peaking around 20 weeks' gestation. Signs of virilization (acne, hirsutism) developed in the mother by 23 weeks' gestation. The mother's hyperandrogenism resolved rapidly after birth. The boy's karyotype was 46,XY and he had normal male genitalia, including descended testes, at birth. There was no evidence of skeletal abnormalities. The unaffected parents were heterozygous for Y181D and C569Y, respectively.
In 2 Japanese sibs and an unrelated Japanese individual with skeletal findings of Antley-Bixler syndrome and abnormal genitalia and/or impaired steroidogenesis (ABS1; 201750), Fukami et al. (2005) identified compound heterozygosity for mutations in the POR gene, one of which was a 1-bp insertion (1329C) in exon 11, resulting in a truncated protein at codon 449. On the other allele, the 2 sibs had a 1733A-G transition in exon 13, resulting in a tyr578-to-cys substitution (Y578C; 124015.0012); the third patient had an R457H mutation in exon 11 (124015.0005).
For discussion of the tyr578-to-cys (Y578C) mutation in the POR gene that was found in compound heterozygous state in patients with skeletal findings of Antley-Bixler syndrome and abnormal genitalia and/or impaired steroidogenesis (ABS1; 201750) by Fukami et al. (2005), see 124015.0011.
In 2 Japanese sibs with skeletal findings of Antley-Bixler syndrome and abnormal genitalia (ABS1; 201750), Fukami et al. (2005) identified compound heterozygosity for a 24-bp deletion in exon 14 of the POR gene, resulting in the loss of 9 amino acids and the creation of 1 amino acid (arg612), and an R457H mutation in exon 11 (124015.0005).
In a Japanese boy with skeletal findings of Antley-Bixler syndrome and abnormal genitalia (ABS1; 201750), Fukami et al. (2005) identified compound heterozygosity for a 15A-G transition in exon 1 of the POR gene, resulting in a 'silent' gly5-to-gly (G5G) substitution, and an R457H mutation in exon 11 (124015.0005). Computerized modeling analysis indicated that the 15A-G transition could disturb an exonic splicing enhancer motif.
In a male infant with skeletal findings of Antley-Bixler syndrome and abnormal steroids and genitalia (ABS1; 201750), in whom Hurley et al. (2004) had previously found a heterozygous missense mutation of unclear significance in the FGFR1 gene (136350.0011), Huang et al. (2005) identified compound heterozygosity for a 13-bp insertion (580insTACGTGGACAAGC) and a gly539-to-arg (G539R; 124015.0016) substitution in the POR gene. The frameshift was predicted to disrupt the flavin mononucleotide (FMN)- and NADPH-binding sites and to result in premature termination of the protein. Functional studies showed that the G539R mutant retained 46% of the 17-alpha-hydroxylase activity but only 8% of the 17,20 lyase activity; consistent with this, the patient was able to synthesize cortisol adequately (17-alpha-hydrolase activity) but had poor production of sex steroids (17,20 lyase activity).
For discussion of the gly539-to-arg (G539R) mutation in the POR gene that was found in compound heterozygous state in a patient with skeletal findings of Antley-Bixler syndrome and abnormal steroids and genitalia (ABS1; 201750) by Huang et al. (2005), see 124015.0015.
Hershkovitz et al. (2008) reported 4 undervirilized males of an extended Bedouin family. One of these had been reported by Biason-Lauber et al. (1997) to carry mutations in the CYP17A1 gene (609300), encoding P450c17, causing isolated 17,20-lyase deficiency (202110). Gas chromatography-mass spectrometry (GC-MS) urinary steroid profiling and serum steroid measurements showed combined deficiencies of 17,20-lyase and 21-hydroxylase. Sequencing of exons 1 and 8 of CYP17A1 in 2 different laboratories showed no mutations. Sequencing of the POR gene showed that all 4 patients were homozygous for a c.1697G-A transition (c.1697G-A, NM_000941) in exon 12 of the POR gene resulting in the G539R amino acid substitution, which was shown by Huang et al. (2005) to retain 46% of normal 17-alpha-hydroxylase activity but only 8% of the 17,20-lyase activity of P450c17. Hershkovitz et al. (2008) concluded that POR deficiency (613571) can masquerade clinically as isolated 17,20-lyase deficiency.
Adachi, M., Asakura, Y., Matsuo, M., Yamamoto, T., Hanaki, K., Arlt, W. POR R457H is a global founder mutation causing Antley-Bixler syndrome with autosomal recessive trait. (Letter) Am. J. Med. Genet. 140A: 633-635, 2006. [PubMed: 16470797] [Full Text: https://doi.org/10.1002/ajmg.a.31112]
Arlt, W., Walker, E. A., Draper, N., Ivison, H. E., Ride, J. P., Hammer, F., Chalder, S. M., Borucka-Mankiewicz, M., Hauffa, B. P., Malunowicz, E. M., Stewart, P. M., Shackleton, C. H. L. Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet 363: 2128-2135, 2004. [PubMed: 15220035] [Full Text: https://doi.org/10.1016/S0140-6736(04)16503-3]
Biason-Lauber, A., Leiberman, E., Zachmann, M. A single amino acid substitution in the putative redox partner-binding site of P450c17 as cause of isolated 17,20-lyase deficiency. J. Clin. Endocr. Metab. 82: 3807-3812, 1997. [PubMed: 9360545] [Full Text: https://doi.org/10.1210/jcem.82.11.4380]
Fluck, C. E., Tajima, T., Pandey, A. V., Arlt, W., Okuhara, K., Verge, C. F., Jabs, E. W., Mendonca, B. B., Fujieda, K., Miller, W. L. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nature Genet. 36: 228-230, 2004. [PubMed: 14758361] [Full Text: https://doi.org/10.1038/ng1300]
Fukami, M., Horikawa, R., Nagai, T., Tanaka, T., Naiki, Y., Sato, N., Okuyama, T., Nakai, H., Soneda, S., Tachibana, K., Matsuo, N., Sato, S., Homma, K., Nishimura, G., Hasegawa, T., Ogata, T. Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. J. Clin. Endocr. Metab. 90: 414-426, 2005. [PubMed: 15483095] [Full Text: https://doi.org/10.1210/jc.2004-0810]
Hershkovitz, E., Parvari, R., Wudy, S. A., Hartmann, M. F., Gomes, L. G., Loewental, N., Miller, W. L. Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency. J. Clin. Endocr. Metab. 93: 3584-3588, 2008. [PubMed: 18559916] [Full Text: https://doi.org/10.1210/jc.2008-0051]
Huang, N., Pandey, A. V., Agrawal, V., Reardon, W., Lapunzina, P. D., Mowat, D., Jabs, E. W., Van Vliet, G., Sack, J., Fluck, C. E., Miller, W. L. Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am. J. Hum. Genet. 76: 729-749, 2005. [PubMed: 15793702] [Full Text: https://doi.org/10.1086/429417]
Hurley, M. E., White, M. J., Green, A. J., Kelleher, J. Antley-Bixler syndrome with radioulnar synostosis. Pediat. Radiol. 34: 148-151, 2004. [PubMed: 14513299] [Full Text: https://doi.org/10.1007/s00247-003-1066-7]
Kelley, R. I., Kratz, L. E., Glaser, R. L., Netzloff, M. L., Wolf, L. M., Jabs, E. W. Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia. Am. J. Med. Genet. 110: 95-102, 2002. [PubMed: 12116245] [Full Text: https://doi.org/10.1002/ajmg.10510]
Miller, W. L. Congenital adrenal hyperplasia. (Letter) New Eng. J. Med. 314: 1321-1322, 1986. [PubMed: 3702935]
Otto, D. M. E., Henderson, C. J., Carrie, D., Davey, M., Gundersen, T. E., Blomhoff, R., Adams, R. H., Tickle, C., Wolf, C. R. Identification of novel roles of the cytochrome P450 system in early embryogenesis: effects on vasculogenesis and retinoic acid homeostasis. Molec. Cell. Biol. 23: 6103-6116, 2003. [PubMed: 12917333] [Full Text: https://doi.org/10.1128/MCB.23.17.6103-6116.2003]
Peterson, R. E., Imperato-McGinley, J., Gautier, T., Shackleton, C. Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases: a new variant of congenital adrenal hyperplasia. New Eng. J. Med. 313: 1182-1191, 1985. [PubMed: 2932643] [Full Text: https://doi.org/10.1056/NEJM198511073131903]
Reardon, W., Smith, A., Honour, J. W., Hindmarsh, P., Das, D., Rumsby, G., Nelson, I., Malcolm, S., Ades, L., Sillence, D., Kumar, D., DeLozier-Blanchet, C., McKee, S., Kelly, T., McKeehan, W. L., Baraitser, M., Winter, R. M. Evidence for digenic inheritance in some cases of Antley-Bixler syndrome? J. Med. Genet. 37: 26-32, 2000. [PubMed: 10633130] [Full Text: https://doi.org/10.1136/jmg.37.1.26]
Shen, A. L., O'Leary, K. A., Kasper, C. B. Association of multiple developmental defects and embryonic lethality with loss of microsomal NADPH-cytochrome P450 oxidoreductase. J. Biol. Chem. 277: 6536-6541, 2002. [PubMed: 11742006] [Full Text: https://doi.org/10.1074/jbc.M111408200]
Shephard, E. A., Phillips, I. R., Santisteban, I., West, L. F., Palmer, C. N., Ashworth, A., Povey, S. Isolation of a human cytochrome P-450 reductase cDNA clone and localization of the corresponding gene to chromosome 7q11.2. Ann. Hum. Genet. 53: 291-301, 1989. [PubMed: 2516426] [Full Text: https://doi.org/10.1111/j.1469-1809.1989.tb01798.x]