Clinical and genetic analysis of cytochrome P450 oxidoreductase (POR) deficiency in a female and the analysis of a novel POR intron mutation causing alternative mRNA splicing
- 28 July 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Assisted Reproduction and Genetics
- Vol. 37 (10), 2503-2511
- https://doi.org/10.1007/s10815-020-01899-z
Abstract
Objective To characterize the clinical features of a female with P450 oxidoreductase (POR) deficiency and to investigate the underlying mechanisms of POR inactivation. Methods The proband was a 35-year-old woman with primary infertility and menstrual irregularity. The reproductive endocrine profile was evaluated. DNA sequencing was conducted for the identification of POR gene mutation. RT-PCR was performed to confirm the impact of the mutation on POR mRNA. A molecular model was built for the structural analysis of mutant POR protein. Results The evaluation of reproductive endocrine profile revealed elevation of serum follicle-stimulating hormone (11.48 mIU/ml), progesterone (11.00 ng/ml), 17α-hydroxyprogesterone (24.24 nmol/l), dehydroepiandrosterone (6300 nmol/l), and androstenedione (3.89 nmol/l) and decreased estradiol (36.02 pg/ml). Sequencing of the POR gene showed the female was a compound heterozygote of the paternal P399_E401 deletion and a novel maternal IVS14-1G>C mutation. Functional analysis revealed IVS14-1G>C mutation caused alternative splicing of POR mRNA, with the loss of 12 nucleotides in exon 15 (c.1898_1909delGTCTACGTCCAG). Also, the resulting mutant POR protein had a V603_Q606 deletion, which inactivated the nucleotide-binding domain of NADPH in POR protein (K602_Q606). Conclusion The mutation IVS14-1G>C of the POR gene could cause alternative splicing of POR mRNA and dysfunction of the resulting POR protein. Under proper IVF strategy with glucocorticoid therapy and endometrial preparation, females with mild POR deficiency still have the opportunity to have a live birth.Keywords
Funding Information
- National Natural Science Foundation of China (2018YFC1002103)
This publication has 43 references indexed in Scilit:
- Clinical, Genetic, and Enzymatic Characterization of P450 Oxidoreductase Deficiency in Four PatientsJournal of Clinical Endocrinology & Metabolism, 2009
- Domain Motion in Cytochrome P450 ReductaseOnline Journal of Public Health Informatics, 2009
- Primary amenorrhea revealing an occult progesterone-secreting ovarian tumorFertility and Sterility, 2008
- Homozygous Mutation G539R in the Gene for P450 Oxidoreductase in a Family Previously Diagnosed as Having 17,20-Lyase DeficiencyJournal of Clinical Endocrinology & Metabolism, 2008
- Genetic and Clinical Features of P450 Oxidoreductase DeficiencyHormone Research in Paediatrics, 2008
- Clinical, structural and functional implications of mutations and polymorphisms in human NADPH P450 oxidoreductaseFundamental & Clinical Pharmacology, 2007
- Diversity and Function of Mutations in P450 Oxidoreductase in Patients with Antley-Bixler Syndrome and Disordered SteroidogenesisAmerican Journal of Human Genetics, 2005
- Identification of Novel Roles of the Cytochrome P450 System in Early Embryogenesis: Effects on Vasculogenesis and Retinoic Acid HomeostasisMolecular and Cellular Biology, 2003
- Association of Multiple Developmental Defects and Embryonic Lethality with Loss of Microsomal NADPH-Cytochrome P450 OxidoreductaseOnline Journal of Public Health Informatics, 2002
- Expression and characterization of truncated human heme oxygenase (hHO-1) and a fusion protein of hHO-1 with human cytochrome P450 reductaseBiochemistry, 1995