Inhibition of placental CYP19A1 activity remains as a valid hypothesis for 46,XX virilization in P450 oxidoreductase deficiency

Flück, Christa E.; Parween, Shaheena; Velazquez, Maria Natalia Rojas; Pandey, Amit V.

doi:10.1073/pnas.2003154117

Cited by 11 publications

(15 citation statements)

References 11 publications

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“…Mutations in POR cause POR deficiency; patients have been described with highly variable clinical and hormonal findings depending on the underlying mutations (66-72 diverts steroids into the 'backdoor pathway' of dihydrotestosterone biosynthesis (Fig. 1), contributing to the prenatal female virilization (69,(78)(79)(80). Second, as placental CYP19 (aromatase) requires POR, pregnant women carrying a fetus with the POR mutation R457H (but not POR A287P) may experience virilization during pregnancy (66-68), similarly to women carrying an aromatase-deficient fetus (81,82).…”

Section: P450 Oxidoreductasementioning

confidence: 99%

Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management

et al. 2021

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Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21- hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000 there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in congenital adrenal hyperplasia with special attention to these new developments.

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Section: P450 Oxidoreductasementioning

confidence: 99%

Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management

et al. 2021

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“…Henceforth, our group started to study how these common variants could affect the healthy carriers without an evident phenotype, especially at the level of drug metabolism. Previous studies of our group have shown that polymorphisms in POR can alter the enzymatic activities of its redox partners [6,[17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 89%

Loss of protein stability and function caused by P228L variation in NADPH-cytochrome P450 reductase linked to lower testosterone levels

Velazquez

Noebauer

Pandey

2022

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Cytochrome P450 oxidoreductase (POR) is the redox partner of steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR cause a broad range of metabolic disorders. The POR variant rs17853284 (P228L) identified by genome sequencing has been linked to lower testosterone levels and reduced P450 activities. We expressed POR wild type and the P228L variant in bacteria, purified the proteins, and performed protein stability and catalytic functional studies. Variant P228L affected the stability of the protein as evidenced by lower unfolding temperatures and higher sensitivity to urea denaturation. A significant reduction of small molecule metabolism was observed with POR P228L while activities of CYP3A4 were reduced by 25%, and activities of CYP3A5, and CYP2C9 were reduced by more than 40% compared to WT POR. The 17,20 lyase activity of CYP17A1 responsible for production of main androgen precursor dehydroepiandrosterone, was reduced to 27% of WT in presence of P228L variant of POR. Based on in silico and in vitro studies we predict that the change of proline to leucine may change the rigidity of the protein, causing conformational changes in POR, leading to altered electron transfer to redox partners. A single amino acid change can affect protein stability and cause a severe reduction in POR activity. Molecular characterization of individual POR mutations is crucial for a better understanding of the impact on different redox partners of POR.

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“…One possible explanation is that certain mutations (e.g. R457H) affect placental P450aro activity leading to maternal and 46,XX fetal virilization during pregnancy due to defective conversion of fetal adrenal C19 androgen precursors to estrogens ( 33 , 61 ). An alternative explanation relies on the excess 17-hydroxyprogesterone conversion to DHT through the “backdoor pathway ( Figure 4 ) ( 22 ).…”

Section: Dsd Associated With Adrenal Disordersmentioning

confidence: 99%

Disorders of Sex Development of Adrenal Origin

et al. 2021

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Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.

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Inhibition of placental CYP19A1 activity remains as a valid hypothesis for 46,XX virilization in P450 oxidoreductase deficiency

Cited by 11 publications

References 11 publications

Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management

Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management

Loss of protein stability and function caused by P228L variation in NADPH-cytochrome P450 reductase linked to lower testosterone levels

Disorders of Sex Development of Adrenal Origin

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