Fukami Maki, Nishimura Gen, Homma Keiko, Nagai Toshiro, Hanaki Keiichi, Uematsu Ayumi, Ishii Tomohiro, Numakura Chikahiko, Sawada Hirotake, Nakacho Mariko, Kowase Takanori, Motomura Katsuaki, Haruna Hidenori, Nakamura Mihoko, Ohishi Akira, Adachi Masanori, Tajima Toshihiro, Hasegawa Yukihiro, Hasegawa Tomonobu, Horikawa Reiko, Fujieda Kenji, Ogata Tsutomu
Research Institute, National Center for Child Health and Development, Tokyo 157-8535, Japan.
J Clin Endocrinol Metab. 2009 May;94(5):1723-31. doi: 10.1210/jc.2008-2816. Epub 2009 Mar 3.
Cytochrome P450 oxidoreductase (POR) deficiency is a rare autosomal recessive disorder characterized by skeletal dysplasia, adrenal dysfunction, disorders of sex development (DSD), and maternal virilization during pregnancy. Although multiple studies have been performed for this condition, several matters remain to be clarified, including the presence of manifesting heterozygosity and the underlying factors for clinical variability.
The objective of the study was to examine such unresolved matters by detailed molecular studies and genotype-phenotype correlations.
Thirty-five Japanese patients with POR deficiency participated in the study.
Mutation analysis revealed homozygosity for R457H in cases 1-14 (group A), compound heterozygosity for R457H and one apparently null mutation in cases 15-28 (group B), and other combinations of mutations in cases 29-35 (group C). In particular, FISH and RT-PCR sequencing analyses revealed an intragenic microdeletion in one apparent R457H homozygote, transcription failure of apparently normal alleles in three R457H heterozygotes, and nonsense mediated mRNA decay in two frameshift mutation-positive cases examined. Genotype-phenotype correlations indicated that skeletal features were definitely more severe, and adrenal dysfunction, 46,XY DSD, and pubertal failure were somewhat more severe in group B than group A, whereas 46,XX DSD and maternal virilization during pregnancy were similar between two groups. Notable findings also included the contrast between infrequent occurrence of 46,XY DSD and invariable occurrence of 46,XX DSD and pubertal growth pattern in group A mimicking that of aromatase deficiency.
The results argue against the heterozygote manifestation and suggest that the residual POR activity reflected by the R457H dosage constitutes the underlying factor for clinical variability in some features but not other features, probably due to the simplicity and complexity of POR-dependent metabolic pathways relevant to each phenotype.
细胞色素P450氧化还原酶（POR）缺乏症是一种罕见的常染色体隐性疾病，其特征为骨骼发育异常、肾上腺功能障碍、性发育障碍（DSD）以及孕期母体男性化。尽管针对该病症已开展多项研究，但仍有若干问题有待阐明，包括显性杂合子的存在情况以及临床变异性的潜在因素。
本研究旨在通过详细的分子研究以及基因型-表型相关性分析来探究这些尚未解决的问题。
35名日本POR缺乏症患者参与了本研究。
突变分析显示，病例1-14（A组）为R457H纯合子，病例15-28（B组）为R457H复合杂合子且伴有一个明显的无效突变，病例29-35（C组）为其他突变组合。具体而言，荧光原位杂交（FISH）和逆转录聚合酶链反应（RT-PCR）测序分析显示，一名明显的R457H纯合子存在基因内微缺失，三名R457H杂合子中看似正常的等位基因转录失败，以及在检测的两例移码突变阳性病例中存在无义介导的mRNA降解。基因型-表型相关性表明，B组的骨骼特征肯定更为严重，肾上腺功能障碍、46,XY DSD和青春期发育失败也比A组更为严重，而两组之间的46,XX DSD和孕期母体男性化情况相似。显著发现还包括A组中46,XY DSD的罕见发生与46,XX DSD和青春期生长模式的不变发生之间的对比，后者类似于芳香化酶缺乏症。
研究结果反驳了杂合子表现的观点，并表明R457H剂量所反映的残余POR活性构成了某些特征而非其他特征临床变异性的潜在因素，这可能是由于与每种表型相关的POR依赖性代谢途径的简单性和复杂性所致。
