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

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.