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.

中文翻译：

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女性细胞色素 P450 氧化还原酶 (POR) 缺乏症的临床和遗传分析以及导致选择性 mRNA 剪接的新型 POR 内含子突变的分析：对 POR 缺乏症女性的总体分析。

客观的

表征女性 P450 氧化还原酶 (POR) 缺乏症的临床特征并研究 POR 失活的潜在机制。

方法

先证者是一名 35 岁的女性，患有原发性不孕症和月经不调。评估生殖内分泌特征。进行DNA测序以鉴定POR基因突变。进行RT-PCR以确认突变对POR mRNA的影响。建立了用于突变POR蛋白结构分析的分子模型。

结果

生殖内分泌特征的评估显示血清促卵泡激素 (11.48 mIU/ml)、孕酮 (11.00 ng/ml)、17α-羟基孕酮 (24.24 nmol/l)、脱氢表雄酮 (6300 nmol/l) 和雄烯二酮 ( 3.89 nmol/l) 和降低的雌二醇 (36.02 pg/ml)。POR基因的测序显示雌性是父本 P399_E401 缺失和新的母本 IVS14-1G>C 突变的复合杂合子。功能分析显示 IVS14-1G>C 突变导致POR mRNA 的选择性剪接，外显子 15 (c.1898_1909delGTCTACGTCCAG) 丢失 12 个核苷酸。此外，所得突变 POR 蛋白具有 V603_Q606 缺失，这使 POR 蛋白（K602_Q606）中 NADPH 的核苷酸结合域失活。

结论

POR基因的突变 IVS14-1G>C可能导致POR mRNA 的选择性剪接和所得 POR 蛋白的功能障碍。在糖皮质激素治疗和子宫内膜准备的适当IVF策略下，轻度POR缺乏的女性仍有机会活产。