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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

Overall analysis of a female with POR deficiency

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

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.

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Acknowledgments

The authors thank everyone in the department of Reproductive Medicine in the Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology (HUST) for their scientific advice and encouragement.

Conflict of interest

The authors declare that they have no competing interests.

Funding

This work was supported by the research grants from:

1. National Key Research and Development Program (China, 2018YFC1002103)

2. The Chinese Medical Association (16020520668)

3. The Natural Science Foundation of Hubei Province (China, 2017CFB752)

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Authors and Affiliations

  1. Reproductive Medicine Center, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, 1095 JieFang Avenue, Wuhan, 430030, People’s Republic of China

    Tao Zhang, Zhou Li, Xinling Ren, Bo Huang, Guijin Zhu, Wei Yang & Lei Jin

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  1. Tao Zhang
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  2. Zhou Li
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  6. Wei Yang
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  7. Lei Jin
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Contributions

Tao Zhang carried out the analysis and interpretation of data and writing of the manuscript. Zhou Li, Bo Huang, and Xinling Ren have been involved in the ultrasound examination and critical manuscript revisions. Lei Jin and Guijin Zhu participated in its design and coordination and helped to draft the manuscript. Wei Yang participated in the conception and design of the study. All authors have read and approved the final version of the manuscript.

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Correspondence to Wei Yang or Lei Jin.

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The study protocol was approved by the Medical Ethics Committee of Tongji Hospital. Written informed consent was obtained from all participants. Research was conducted according to the Declaration of Helsinki for medical research.

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Clinical and genetic analysis of POR deficiency in a female.

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Zhang, T., Li, Z., Ren, X. et al. 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. J Assist Reprod Genet 37, 2503–2511 (2020). https://doi.org/10.1007/s10815-020-01899-z

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  • DOI: https://doi.org/10.1007/s10815-020-01899-z

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