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P450 oxidoreductase (POR; HGNC:9208) encodes the flavoprotein that donates electrons from NADPH to all microsomal cytochrome P450 enzymes. Autosomal recessive POR mutations cause a rare form of congenital adrenal hyperplasia (CAH; MONDO:0018479) characterized by combined partial deficiencies of CYP17A1, CYP21A2, and CYP19A1 activities, with clinical features of adrenal insufficiency, disorders of sexual development, and skeletal malformations ([PMID:19500762]). POR deficiency was first identified in patients presenting with apparent combined 17α-hydroxylase and 21-hydroxylase deficiencies without mutations in the CYP17A1 or CYP21A2 genes, implicating POR as the underlying genetic cause of this CAH variant ([PMID:15666840]).
Extensive case series and multi-center studies have documented biallelic POR variants in over 65 affected individuals from more than 20 unrelated families, consistently demonstrating autosomal recessive inheritance and genotype–phenotype correlation ([PMID:21164260]). Segregation analysis in multiplex pedigrees has confirmed co-segregation of pathogenic POR alleles with disease across first- and second-degree relatives, totaling at least 19 affected relatives with matching genotypes. Both loss-of-function (nonsense, frameshift, splice) and missense variants distributed across the FMN, FAD, and NADPH-binding domains have been reported. A recurrent founder variant, c.1370G>A (p.Arg457His), accounts for a substantial proportion of pathogenic alleles in multiple populations.
Clinically, POR deficiency presents with variable adrenal insufficiency and impaired sex steroid biosynthesis leading to ambiguous genitalia in 46,XY individuals and virilization in 46,XX patients. Unique features of P450 oxidoreductase deficiency include Antley–Bixler-like skeletal malformations (craniosynostosis, radiohumeral synostosis) and maternal virilization during pregnancy due to impaired placental aromatase activity ([PMID:16467261]). Hypergonadotropic hypogonadism, ovarian cysts, hirsutism, and acne have also been observed, reflecting multisystem involvement of POR in steroidogenic and non-steroidogenic P450 pathways.
Functional studies of POR variants using recombinant protein and cell-based assays have demonstrated variant-specific decreases in electron transfer to partner P450 enzymes. Common assays include cytochrome c reduction, steroidogenic enzyme assays for 17α-hydroxylase, 17,20-lyase, 21-hydroxylase, and aromatase activities, and rescue experiments with exogenous flavin cofactors. For instance, the c.1370G>A (p.Arg457His) mutation reduces POR activity by >90% across multiple assays and disrupts FAD binding, confirming a loss-of-function mechanism ([PMID:16467261]; [PMID:15666840]). Additional variants such as A287P and Y459H show differential effects on CYP17A1 versus CYP21A2, providing mechanistic insights into phenotypic heterogeneity ([PMID:17505056]).
No significant conflicting evidence has emerged; all reported POR mutations in CAH patients show concordant genetic and functional data supporting pathogenicity. The rarity of POR deficiency and its complex phenotype underscore the need for genetic testing in atypical CAH cases and for functional characterization of novel variants.
In summary, POR deficiency is a well-established autosomal recessive cause of congenital adrenal hyperplasia with definitive genetic and functional evidence. Recognition of POR as a CAH gene enables accurate diagnosis, genetic counseling, and tailored management. Key Take-home: Genetic testing for POR variants should be included in CAH diagnostic panels, especially in patients with combined steroidogenic defects and skeletal anomalies.
Gene–Disease AssociationDefinitive≥65 probands with biallelic POR variants across >20 unrelated families; autosomal recessive inheritance; extensive functional concordance ([PMID:21164260]) Genetic EvidenceStrongBiallelic variants in ≥65 patients; multiple variant classes including LoF and missense with segregation and recurrence ([PMID:21164260]) Functional EvidenceModerateRecombinant POR assays and cell models demonstrate variant-specific loss of electron transfer to multiple P450 enzymes, consistent with human phenotype ([PMID:15666840]; [PMID:16467261]) |