Preprint Article Version 1 This version is not peer-reviewed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)

How to cite: Parween, S.; Fernández Cancio, M.; Benito-Sanz, S.; Camats, N.; Velazquez, M.N.R..; López-Siguero, J.; Udhane, S.S.; Kagawa, N.; Flück, C..; Audì, L..; Pandey, A. 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. Preprints 2019, 2019090103 (doi: 10.20944/preprints201909.0103.v1). Parween, S.; Fernández Cancio, M.; Benito-Sanz, S.; Camats, N.; Velazquez, M.N.R..; López-Siguero, J.; Udhane, S.S.; Kagawa, N.; Flück, C..; Audì, L..; Pandey, A. 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. Preprints 2019, 2019090103 (doi: 10.20944/preprints201909.0103.v1).

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.

Supplementary and Associated Material

http://www.pandeylab.org: Author Website

Subject Areas

PORD; congenital adrenal hyperplasia; POR; CY19A1; CYP21A2, CYP17A1

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