A CONSTITUTIVELY ACTIVATING MUTATION OF THE LUTEINIZING-HORMONE RECEPTOR IN FAMILIAL MALE PRECOCIOUS PUBERTY
A CONSTITUTIVELY ACTIVATING MUTATION OF THE LUTEINIZING-HORMONE RECEPTOR IN FAMILIAL MALE PRECOCIOUS PUBERTY
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DOI：
10.1038/365652a0
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发表时间：
1993-10-14
期刊：
影响因子：
64.8
通讯作者：
CUTLER, GB
中科院分区：
文献类型：
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作者：
SHENKER, A;LAUE, L;CUTLER, GB
家族性男性性早熟（FMP）是一种不依赖促性腺激素的疾病，以常染色体显性遗传，男性限制模式遗传1-5。受影响的男性通常在4岁时表现出青春期的迹象。睾丸激素的产生和间质细胞的增生发生在青春期前黄体生成素（LH）水平3-5的背景下。LH受体是g蛋白偶联受体家族的一员6,7，我们假设FMPP可能是由于在很少或没有激动剂存在时激活的突变受体8-12。在8个不同家族的受影响个体中发现了单个A -> G碱基变化，导致在LH受体第6跨膜螺旋578位甘氨酸取代天冬氨酸。限制性消化分析支持突变与FMPP的连锁关系。在缺乏激动剂的情况下，表达突变LH受体的COS-7细胞表现出明显增加的环AMP产生，这表明FMPP中自主间质细胞活性是由组成性激活的LH受体引起的。
FAMILIAL male precocious puberty (FMP) is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern1-5. Affected males generally exhibit signs of puberty by age 4. Testosterone production and Leydig cell hyperplasia occur in the context of prepubertal levels of luteinizing hormone (LH)3-5. The LH receptor is a member of the family of G-protein-coupled receptors6,7, and we hypothesized that FMPP might be due to a mutant receptor that is activated in the presence of little or no agonist8-12 . A single A --> G base change that results in substitution of glycine for aspartate at position 578 in the sixth transmembrane helix of the LH receptor was found in affected individuals from eight different families. Linkage of the mutation to FMPP was supported by restriction-digest analysis. COS-7 cells expressing the mutant LH receptor exhibited markedly increased cyclic AMP production in the absence of agonist, suggesting that autonomous Leydig cell activity in FMPP is caused by a constitutively activated LH receptor.