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

Parween, Shaheena; Fernández-Cancio, Mónica; Benito-Sanz, Sara; Camats, Núria; Rojas Velazquez, Maria Natalia; López-Siguero, Juan-Pedro; Udhane, Sameer S; Kagawa, Norio; Flück, Christa E; Audí, Laura; Pandey, Amit Vikram (2020). Molecular Basis of CYP19A1 Deficiency in a 46,XX Patient With R550W Mutation in POR: Expanding the PORD Phenotype. The journal of clinical endocrinology and metabolism, 105(4), e1272-e1290. Oxford University Press 10.1210/clinem/dgaa076

[img]
Preview
Text
dgaa076.pdf - Accepted Version
Available under License Publisher holds Copyright.

Download (1MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Endocrinology/Metabolic Disorders

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Parween, Shaheena; Rojas Velazquez, Maria Natalia; Udhane, Sameer Sopanrao; Flück Pandey, Christa Emma and Pandey, Amit Vikram

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1945-7197

Publisher:

Oxford University Press

Funders:

[4] Swiss National Science Foundation ; [UNSPECIFIED] Novartis foundation for medical biological research

Language:

English

Submitter:

Amit Vikram Pandey

Date Deposited:

08 Jun 2020 12:03

Last Modified:

18 May 2021 07:44

Publisher DOI:

10.1210/clinem/dgaa076

PubMed ID:

32060549

Additional Information:

Originalarbeit gemäss L.S.

Uncontrolled Keywords:

CY19A1 CYP17A1 CYP21A2 POR PORD congenital adrenal hyperplasia

BORIS DOI:

10.7892/boris.144443

URI:

https://boris.unibe.ch/id/eprint/144443

Actions (login required)

Edit item Edit item
Provide Feedback