新的见解的分子基础3 beta-hydroxysteroid脱氢酶缺乏症:识别8 HSD3B2基因的突变11从七个新病人家庭和25突变酶的功能性质的比较。
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Moisan,特ML,迟缓的V, Desrochers M, Mebarki F, Chaussain杰,卡布罗尔年代,Raux-Demay MC,森林毫克,Sippell WG,彼得·米莱尔Y, Simard J
新的见解的分子基础3 beta-hydroxysteroid脱氢酶缺乏症:识别8 HSD3B2基因的突变11从七个新病人家庭和25突变酶的功能性质的比较。
中国性金属底座。1999年12月,84(12):4410 - 25所示。
- PubMed ID
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10599696 (在PubMed]
- 文摘
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经典3 beta-hydroxysteroid脱氢酶/ delta5-delta4异构酶(3 betahsd)缺乏症是一种先天性肾上腺增生,损害所导致的肾上腺和性腺类固醇生成HSD3B2基因的突变,导致不同程度的salt-wasting两性和不完整的男性化基因的雄性外生殖器的。识别分子病变(s)在HSD3B2基因11个病人从七个新家庭遭受古典3 betahsd缺乏完整的整个编码区核苷酸序列和exon-intron拼接边界的这种基因是由直接测序。五个家庭被称为莫雷尔的分子诊断实验室在法国,而另外两个家庭在德国进行了彼得的组。功能描述在加拿大Simard的小组所进行的研究。293年后瞬时表达细胞的定点诱变产生的突变重组蛋白,25突变对酶活性的影响评估孵化完整细胞在文化与10 nM [14 c]脱氢表雄酮作为衬底。突变蛋白的稳定性一直是研究使用北部和免疫印迹分析,以及体外转录/翻译分析使用兔网织红细胞溶解产物。本报告描述了8突变的识别,在七个新家庭和个人遭受古典3 betahsd不足,从而增加已知HSD3B2突变的数量参与这常染色体隐性障碍31(1拼接,1在坐标系删除3胡说,4转移和22个错义突变)。除了突变报道在这些新家庭,我们也首次调查之前报道的功能意义错义突变和或序列变异即A82T, A167V, L173R, L205P, S213G K216E, P222H, T259M, T259R,以前没有的功能特点。此外,他们的影响已经比之前报道的10突变酶提供更一致的和全面的研究。目前的结果是按照预测,没有功能3 betahsd 2型同工酶表达在肾上腺和性腺的病人患有一种严重salt-wasting CAH由于古典3 betahsd缺乏症。 Whereas the nonsalt-losing form also results from missense mutation(s) in the HSD3B2 gene, which cause an incomplete loss in enzyme activity, thus leaving sufficient enzymatic activity to prevent salt wasting. The functional data described in the present study concerning the sequence variants A167V, S213G, K216E and L236S, which were detected with premature pubarche or hyperandrogenic adolescent girls suspected to be affected from nonclassical 3betaHSD deficiency, coupled with the previous studies reporting that no mutations were found in both HSD3B1 and/or HSD3B2 genes in such patients strongly support the conclusion that this disorder does not result from a mutant 3betaHSD isoenzyme. The present study provides biochemical evidence supporting the involvement of a new molecular mechanism in classical 3betaHSD deficiency involving protein instability and further illustrates the complexity of the genotype-phenotype relationships of this disease, in addition to providing further valuable information concerning the structure-function relationships of the 3betaHSD superfamily.