Hereditary Male Pseudohermaphroditism Associated with an Unstable Form of 5α-Reductase
Hereditary Male Pseudohermaphroditism Associated with an Unstable Form of 5α-Reductase
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与不稳定形式的 5α-还原酶相关的遗传性男性假两性畸形
DOI：
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发表时间：
1978
期刊：
影响因子：
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通讯作者：
Jean D. Wilson
中科院分区：
文献类型：
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作者：
M. Leshin;J. Griffin;Jean D. Wilson
在来自三个家族（洛杉矶、达拉斯和多米尼加共和国）的5名患者培养的生殖器皮肤成纤维细胞中，比较了5 α还原酶的特性，这些患者的遗传性男性假两性畸形是由于睾酮向双氢睾酮的转化不足造成的。尽管从一名洛杉矶患者身上取下的附睾匀浆中检测不到5α -还原酶，但在来自洛杉矶家族的两名患者的完整成纤维细胞和成纤维细胞提取物中，5α -还原酶活性是正常的。虽然睾酮的表观K(m)也接近正常，但这些突变体中NADPH的表观K(m)比正常高约40倍。此外，在45℃条件下，NADPH浓度稳定正常的5 α -还原酶不能保护酶不变性，并且在这些患者（而不是对照组）的完整成纤维细胞中，当蛋白质合成受到抑制时，酶活性会迅速下降。我们得出结论，这个家族的突变导致了一种不稳定的酶。相比之下，多米尼加共和国家族患者的成纤维细胞提取物中的5 - α还原酶活性与之前在达拉斯家族的两个成员中描述的相似，即在正常反应的最佳pH下，总酶活性较低，睾酮的表观K(m)比对照高约20倍。我们得出结论，达拉斯和多米尼加共和国家族的突变是相似的，并且由于对睾酮的亲和力降低，导致酶活性降低。因此，由于缺乏双氢睾酮的形成，两种不同类型的突变可以产生男性假雌雄同体。
The properties of 5alpha-reductase have been compared in genital skin fibroblasts cultured from five patients from three families (Los Angeles, Dallas, and Dominican Republic) in which hereditary male pseudohermaphroditism has been established to result from deficient conversion of testosterone to dihydrotestosterone. Despite the fact that 5alpha-reductase was immeasurable in a homogenate of epididymis removed from one of the Los Angeles patients, 5alpha-reductase activity was normal in intact fibroblasts and fibroblast extracts from both patients from the Los Angeles family. Although the apparent K(m) for testosterone was also near normal, the apparent K(m) for NADPH in these mutants is elevated some 40-fold above normal. Furthermore, the enzyme is not protected against denaturation at 45 degrees C by concentrations of NADPH that stabilize normal 5alpha-reductase, and in intact fibroblasts from these patients (but not from controls), enzyme activity decreases promptly when protein synthesis is inhibited. We conclude that the mutation in this family results in an unstable enzyme. In contrast 5alpha-reductase activity in fibroblast extracts from a patient from the Dominican Republic family is similar to that previously described in two members of the Dallas family, namely total enzyme activity is low at the optimal pH for the normal reaction, and the apparent K(m) for testosterone is some 20-fold higher than that of the controls. We conclude that the mutations in the Dallas and Dominican Republic families are similar and result in low activity of the enzyme as the result of a decreased affinity for testosterone.Thus, two distinct types of mutations can produce male pseudohermaphroditism due to deficient dihydrotestosterone formation.