PreprintArticleVersion 1Preserved in Portico This version is not peer-reviewed
Molecular Basis of Aromatase Deficiency in a 46, XX Patient with Mutation of Arginine 550 to Tryptophan in POR: Expanding the Endocrine Phenotype in PORD
Version 1
: Received: 7 September 2019 / Approved: 9 September 2019 / Online: 9 September 2019 (14:48:39 CEST)
Version 2
: Received: 11 February 2020 / Approved: 12 February 2020 / Online: 12 February 2020 (02:57:08 CET)
Shaheena Parween, Mónica Fernández-Cancio, Sara Benito-Sanz, Núria Camats, Maria Natalia Rojas Velazquez, Juan-Pedro López-Siguero, Sameer S Udhane, Norio Kagawa, Christa E Flück, Laura Audí, Amit V Pandey, Molecular basis of CYP19A1 deficiency in a 46, XX patient with R550W mutation in POR: Expanding the PORD phenotype, The Journal of Clinical Endocrinology & Metabolism, , dgaa076, https://doi.org/10.1210/clinem/dgaa076
Shaheena Parween, Mónica Fernández-Cancio, Sara Benito-Sanz, Núria Camats, Maria Natalia Rojas Velazquez, Juan-Pedro López-Siguero, Sameer S Udhane, Norio Kagawa, Christa E Flück, Laura Audí, Amit V Pandey, Molecular basis of CYP19A1 deficiency in a 46, XX patient with R550W mutation in POR: Expanding the PORD phenotype, The Journal of Clinical Endocrinology & Metabolism, , dgaa076, https://doi.org/10.1210/clinem/dgaa076
Shaheena Parween, Mónica Fernández-Cancio, Sara Benito-Sanz, Núria Camats, Maria Natalia Rojas Velazquez, Juan-Pedro López-Siguero, Sameer S Udhane, Norio Kagawa, Christa E Flück, Laura Audí, Amit V Pandey, Molecular basis of CYP19A1 deficiency in a 46, XX patient with R550W mutation in POR: Expanding the PORD phenotype, The Journal of Clinical Endocrinology & Metabolism, , dgaa076, https://doi.org/10.1210/clinem/dgaa076
Shaheena Parween, Mónica Fernández-Cancio, Sara Benito-Sanz, Núria Camats, Maria Natalia Rojas Velazquez, Juan-Pedro López-Siguero, Sameer S Udhane, Norio Kagawa, Christa E Flück, Laura Audí, Amit V Pandey, Molecular basis of CYP19A1 deficiency in a 46, XX patient with R550W mutation in POR: Expanding the PORD phenotype, The Journal of Clinical Endocrinology & Metabolism, , dgaa076, https://doi.org/10.1210/clinem/dgaa076
Abstract
Context: Mutations in Cytochrome P450 oxidoreductase (POR) cause a form of congenital adrenal hyperplasia (CAH). We are reporting a novel R550W mutation in POR identified in a 46, XX patient with signs of aromatase deficiency. Objective: Analysis of aromatase deficiency from R550W mutation in POR. Design, Setting, and Patient: Both the child and the mother had signs of virilization. Ultrasound revealed the presence of uterus and ovaries. No defects in CYP19A1 were found, but further analysis with a targeted Disorders of Sexual Development NGS panel (DSDSeq.V1, 111 genes) on a NextSeq (Illumina) platform in Madrid and Barcelona, Spain, revealed compound heterozygous mutations c.73_74delCT/p.L25FfsTer93 and c.1648C>T/p.R550W in POR. WT and R550W POR were produced as recombinant proteins and tested with multiple cytochrome P450 enzymes at University Children’s Hospital, Bern, Switzerland. Main Outcome Measure and Results: R550W POR showed 41% of the WT activity in cytochrome c and 7.7% activity for reduction of MTT. Assays of CYP19A1 showed a severe loss of activity and CYP17A1, as well as CYP21A2 activities, were also lost by more than 95%. Loss of CYP2C9, CYP2C19, and CYP3A4 activities was observed for the R550W-POR. Predicted adverse effect on aromatase activity as well as a reduction in binding of NADPH was confirmed. Conclusions: Pathological effects due to POR R550W were identified, expanding the knowledge of molecular pathways associated with aromatase deficiency. Screening of the POR gene may provide a diagnosis in CAH without defects in genes for steroid metabolizing enzymes.
Biology and Life Sciences, Endocrinology and Metabolism
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
