Molecular Basis of CYP19A1 Deficiency in a 46,XX Patient With R550W Mutation in POR: Expanding the PORD Phenotype.

Abstract

CONTEXT:

Mutations in cytochrome P450 oxidoreductase (POR) cause a form of congenital adrenal hyperplasia (CAH). We report a novel R550W mutation in POR identified in a 46,XX patient with signs of aromatase deficiency.

OBJECTIVE:

Analysis of aromatase deficiency from the 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. Wild-type 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:

POR-R550W 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.

• Authors: 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
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 105 Issue 4 (04 01 2020) ISSN: 1945-7197 [Electronic] United States
• PMID: 32060549 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Aromatase
• CYP19A1 protein, human

Topics

• 46, XX Disorders of Sex Development (genetics, pathology)
• Adrenal Hyperplasia, Congenital (genetics, pathology)
• Aromatase (deficiency, genetics)
• Child
• Female
• Humans
• Male
• Mutation
• Pedigree
• Phenotype
• Prognosis