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, thermolability . The protein denatures at body temperature (37°C). So at normal body temperatures, both in the presence and absence of bound ligand the mutant G protein was inactive.(正常体温时，不管有无配体结合，G蛋白都处于失活状态) ●

highlighting amino acids changed by point mutations that cause human endocrine diseases. Replacement of either cyan residue produces an inactive G protein alpha subunit, causing pseudohypoparathyroidism.

the parathyroid glands’ normal temperature is 37°C, so the mutation in this same Gα subunit caused the G protein to remain inactive. 甲状旁腺的正常温度是37°C，所以在甲状旁腺细胞中，同样的Gα突变却致使G蛋白处于失活状态。

As a result, the cells of the parathyroid gland could not respond to stimuli that would cause them to secrete parathyroid hormone, leading to the condition of pseudohypoparathyroidism. 其结果是，能使正常甲状旁腺细胞分泌甲状旁腺激素的刺激，却不能使携带Gα亚基突变的甲状旁腺细胞作出应答反应，因而导致假性甲状旁腺功能减退症状。

(A) Rates of GTP[γS] binding. (B) cAMP synthesis stimulated by different concentrations of s or s-R231H

假性甲状旁腺功能减退的症状：A.双手第4、5掌骨对称性变短。B.双足第3、4跖骨对称性变短。C.肱骨干骺部不规则硬化。 An X-ray of the left hand demonstrates shortening of the fourth metacarpal.

B. bilateral shortening of first and fourth right toes. A. bilateral shortening of first, second and fourth fingers.

The fact that most of the bodily organs functioned in a normal manner in these patients suggests that this particular Gα isoform is not essential in the activities of most other cells. 患者身上的大多数器官功能正常，这说明Gα异构体对大多数其它细胞活性而言是不必需的

Disease susceptibility and genetic polymorphisms 疾病易感性和基因多态现象

Gene polymorphisms are thought of as common within the population Gene polymorphisms are thought of as common within the population. Yet it has become clear in recent years that genetic polymorphism may cause certain individuals to be more or less susceptible to particular disorders than other individuals. 基因多态性是一种很普遍的现象，但近些年它被认为能导致一些特定的个体比其他个体对某种疾病更加易感。

This has been well documented in the case of GPCRs. Certain alleles of the gene encoding the β2 adrenergic receptor have been associated with an increased likelihood of asthma or high blood pressure. 编码β2肾上腺素受体的等位基因与增加哮喘或高血压发病率的可能性有关。 ●

多巴胺受体基因与增加得精神分裂症的危险有关。 Certain alleles of a dopamine receptor are associated with increased risk of substance abuse or schizophrenia. 多巴胺受体基因与增加得精神分裂症的危险有关。 ●

一些基因与延长HIV感染个体存活时间有关。 Certain alleles of a gene are associated with prolonged survival in HIV-infected individuals. 一些基因与延长HIV感染个体存活时间有关。 ● Identifying associations between disease susceptibility and genetic polymorphisms is a current focus of clinical research.

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