性早熟和假性甲状旁腺功能减退 医学教学课件

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1、Precociouspubertyandpseudohypoparathyroidism性早熟和假性甲状旁腺功能减退MutationsingenesthatcodeforthesubunitsofheterotrimericGproteinscanleadtoinheriteddisorders.(编码异源三聚体的基因可能导致遗传性疾病)IwillintroduceadiseasethatleadedbyakindofmutationinGαisoforms.Twomalepatientssufferingfrom

2、ararecombinationofendocrinedisorders:Precociouspubertyandpseudohypoparathyroidism.(性早熟和假性甲状旁腺功能减退综合症)ThissyndromeiscausedbyasingleaminoacidsubstitutioninoneoftheGαisoforms.(这种综合征是由Gα异构体上的单个氨基酸替换引起的)Substitutionofaserineforaconservedalanineatposition366inalpha-

3、scausedthiscombinationofraredisordersintwounrelatedpatients.(丝氨酸取代了366位的精氨酸，导致了这种罕见的综合症。)ThealterationinaminoacidsequencecausedtwoeffectsonthemutantGprotein.Attemperaturesbelownormalbodytemperature,eventhoughintheabsenceofaboundligand,themutantGproteinremained

4、intheactivestate.(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)●Themutationactivatesalpha-sbyacceleratingreleaseofboundGDP,whichisthenreplacedbyGTP.Normally,theendocrinecellsofthetestesproducttestosteroneatthetimeofpubertyinresponsetothepituitaryhormoneLH,whichbeginstobep

5、roducedatthattime.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。LHcanbindstothereceptorsonthesurfaceofthetesticularcells,inducingthesynthesisofcAMPandsubsequentproductionofthemalesexhormone.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。Butthetesteshavealowertem

6、peraturethanthebody’svisceralorgans(33°Cvs.37°C).SothetesticularcellsofthepatientsbearingtheGproteinmutationwerestimulatedtosynthesizecAMPintheabsenceoftheLHligand.Thatleadstoprematuresynthesisoftestosteroneandprecociouspuberty.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

7、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。pseudohypoparathyroidisminthesepatientsiscausedbyasecondeffectofthemutation,thermolability.Theproteindenaturesatbodytemperature(37°C).Soatnormalbodytemperatures,bothinthepresenceandab

8、senceofboundligandthemutantGproteinwasinactive.(正常体温时，不管有无配体结合，G蛋白都处于失活状态)●highlightingaminoacidschangedbypointmutationsthatcausehumanendocrinediseases.Replacementofeithercyanresid