性早熟和假性甲状旁腺功能减退 医学教学课件.ppt

* * Precocious puberty and pseudohypoparathyroidism 性早熟和假性甲状旁腺功能减退 Mutations in genes that code for the subunits of heterotrimeric G proteins can lead to inherited disorders. (编码异源三聚体的基因可能导致遗传性疾病) I will introduce a disease that leaded by a kind of mutation in Gα isoforms. Two male patients suffering from a rare combination of endocrine disorders: Precocious puberty and pseudohypoparathyroidism. (性早熟和假性甲状旁腺功能减退综合症) This syndrome is caused by a single amino acid substitution in one of the Gα isoforms. (这种综合征是由Gα异构体上的单个氨基酸替换引起的) Substitution of a serine for a conserved alanine at position 366 in alpha-s caused this combination of rare disorders in two unrelated patients. (丝氨酸取代了366位的精氨酸，导致了这种罕见的综合症。) The alteration in amino acid sequence caused two effects on the mutant G protein. At temperatures below normal body temperature, even though in the absence of a bound ligand, the mutant G protein remained in the active state.(低于正常体温时，即使没有配体的结合，突变体G蛋白也维持着活化状态) ● The mutation activates alpha-s by accelerating release of bound GDP, which is then replaced by GTP. Normally, the endocrine cells of the testes product testosterone at the time of puberty in response to the pituitary hormone LH, which begins to be produced at that time. 在正常体温下，睾丸的内分泌细胞在青春期才会对垂体激素LH做出反应而产生睾酮，LH也是在青春期开始形成的。 LH can binds to the receptors on the surface of the testicular cells, inducing the synthesis of cAMP and subsequent production of the male sex hormone. LH结合于睾丸细胞表面的LH受体，诱导cAMP的合成和随后雄性激素睾酮的产生。 But the testes have a lower temperature than the body’s visceral organs(33°C vs. 37°C). So the testicular cells of the patients bearing the G protein mutation were stimulated to synthesize cAMP in the absence of the LH ligand. That leads to premature synthesis of testosterone and precocious puberty. 但是睾丸的温度低于人体内脏器官的温度，因此正如前面所说的，携带G蛋白突变的患者的睾丸细胞在没有LH配体存在时也能合成cAMP。这将导致睾酮的提早合成和性早熟。 在低浓度的LH存在时，突变体产生cAMP的量与正常人的比较。 pseudohypoparathyroidism in these patients is caused by a second effect of the mutation, th