Nonsalt-losing男性假两性畸形由于小说纯合子n100 II型3 beta-hydroxysteroid脱氢酶基因的突变。
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桑切斯Mebarki F R, Rheaume E, Laflamme N, Simard J,森林毫克,Bey-Omar F, F莱柏瑞,大卫·米莱尔Y
Nonsalt-losing男性假两性畸形由于小说纯合子n100 II型3 beta-hydroxysteroid脱氢酶基因的突变。
中国性金属底座。1995年7月,80 (7):2127 - 34。
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7608265 (在PubMed]
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最近,两个基因编码的结构同功酶负责3 beta-hydroxysteroid脱氢酶/δ5-delta 4-isomerase(3βHSD)活动在人类被阐明。这个活动是一个重要的步骤在所有类的生物合成的类固醇激素。在经典的严重形式的3βHSD缺陷,患者出现肾上腺机能不全,不同程度的盐损失和不完整的男性的男性化。这里我们报告先天性肾上腺增生的分子基础的表征由于3βHSD缺乏来自血缘的父母和没有出生的男性假两性畸形临床盐的损失。分析结构的I型和II 3βHSD基因病人的DNA片段,生成的聚合酶链反应扩增的四个外显子和这些基因的exon-intron边界,直接测序。病人带着一个纯合子的错义突变转换Asn100 Ser的外显子3 II型3βHSD基因。他的父母都是杂合的点突变。缺乏临床盐损失与男性假两性畸形相关建议3βHSD活动是睾丸和肾上腺中不同程度受损。阐明是否n100错义突变优先steroidogenic通路的影响,分析了酶活性在体外分析定点诱变产生的突变酶重组后瞬时表达COS-1细胞。使用从转染细胞匀浆,n100 3βHSD酶显示孕烯醇酮的Km值25 + / - 3 mumol / L与3.5 + / - 0.2 mumol / L正常人II型3βHSD酶。 Similar results were obtained using dehydroepiandrosterone as substrate. In addition to decreasing apparent affinity, the N100S mutation decreased the relative specific activity (Vmax), leading to a relative specificity (relative Vmax/Km) 2.7% and 11% that of normal type II 3 beta HSD using pregnenolone or dehydroepiandrosterone as substrate, respectively. Moreover, the mutant N100S protein had an apparent decreased affinity for NAD+, with a Km value of 650 +/- 66 mumol/L compared with 20 +/- 2 mumol/L for normal type II 3 beta HSD. Except for the hypothetical effect of local factors, these findings suggest that a very weak residual activity of the normal type II 3 beta HSD enzyme could prevent salt loss, but it was insufficient for normal male sex differentiation.(ABSTRACT TRUNCATED AT 400 WORDS)