Cytochrome P450 Oxidoreductase Deficiency: Identification and Characterization of Biallelic Mutations and Genotype-Phenotype Correlations in 35 Japanese Patients
Cytochrome P450 Oxidoreductase Deficiency: Identification and Characterization of Biallelic Mutations and Genotype-Phenotype Correlations in 35 Japanese Patients
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DOI：
10.1210/jc.2008-2816
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发表时间：
2009-05-01
影响因子：
5.8
通讯作者：
Ogata, Tsutomu
中科院分区：
文献类型：
--
作者：
Fukami, Maki;Nishimura, Gen;Ogata, Tsutomu
内容：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遗传疾病，其特征是骨骼发育不良、肾上腺功能障碍、性发育障碍（DSD）和妊娠期母体男性化。虽然对这种情况已经进行了多项研究，但仍有几个问题有待澄清，包括表现杂合性的存在和临床变异的潜在因素。目的：本研究的目的是通过详细的分子研究和基因型-表型相关性来检查这些未解决的问题。患者：35名日本POR缺陷患者参加了本研究。突变分析显示病例1-14（A组）为R457 H纯合性，病例15-28（B组）为R457 H复合杂合性和一个明显无效突变，病例29-35（C组）为其他突变组合。特别是，荧光原位杂交和RT-PCR测序分析显示，在一个明显的R457 H纯合子，转录失败的明显正常等位基因在三个R457 H杂合子，和无义介导的mRNA衰变在两个移码突变阳性的情况下检查基因内微缺失。基因型-表型相关性表明，B组的骨骼特征明显更严重，肾上腺功能障碍、46，XY DSD和青春期衰竭比A组更严重，而46，XX DSD和妊娠期母体男性化在两组之间相似。值得注意的发现还包括46，XY DSD的罕见发生与46，XX DSD的恒定发生之间的对比，以及A组中模仿芳香化酶缺乏的青春期生长模式。结果反对杂合子表现，并表明R457 H剂量反映的残留POR活性构成了某些特征而非其他特征的临床变异性的潜在因素，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。（临床内分泌代谢杂志94：1723-1731，2009）
Context: 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.Objective: The objective of the study was to examine such unresolved matters by detailed molecular studies and genotype-phenotype correlations.Patients: Thirty-five Japanese patients with POR deficiency participated in the study.Results: 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.Conclusions: 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. (J Clin Endocrinol Metab 94: 1723-1731, 2009)