先天性肾源性尿崩症（cndi）_ 首都师范大学课件

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1、DiseasesAssociatedwithGprotein-CoupledReceptorsGivingBywangnishaXiexixiuZhangwenshanWangjingbriefintroductionThehumangenomemayencodeasmanyas2000differentGPCRs.Theirimportanceinhumanbiologyisreflectedbythefactthatmorethanone-quarterofallprescriptiondrugsactasligandsthatbind

2、tothishugesuperfamilyofreceptors.AnumberofinheriteddisordershavebeentracedtodefectsinbothGPCRsandheterotrimericGprotein.SeveraldiseasesCongenitalnephrogenicdiabetesinsipidus(CNDI)Congenitalnephrogenicdiabetesinsipidus(CNDI)isarareinheriteddiseaseinwhichinfantssufferserious

3、dehydrationastheresultofaninabilityoftheirkidneystoproduceaconcentratedurine.Ifnotdiagnosedpromptly,thechronicdehydrationcanproducementalretardation,inadequategrowth,andevendeath.CNDI先天性肾源性尿崩症疾病属性：罕见的遗传性疾病主要症状：由于肾脏集合管对抗利尿激素不起反应而致尿浓缩障碍，出现多饮、多尿和尿比重降低。患病的婴儿的肾脏缺乏产生终尿的能力，他们会遭受到

4、严重的脱水。如果没有及时地诊断治疗，这种慢性的的脱水会引发智障碍、生长迟缓、甚至是死亡.病理检查：抗利尿激素受体发生错误造成信号传导问题，导致CNDI肾脏的细胞失去了对抗利尿激素的应答能力.1Thecauseofthediseaseresultfrommutationsinaquaporins,Thewaterchannelsoftheplasmamembrane.Thecauseofthedisease图示为肾脏的水通道蛋白(Aquaporin-2)，这是一个六次跨膜的蛋白质，氮末端和碳末端都在膜内，有三个细胞外环和两个细胞内环。图上的黑

5、点表示突变位点，这些突变位点的变化导致水通道蛋白的失活或通透性增强，相应表现为病人脱水或不排尿。相应于CNDI的突变为Q57POtherreasonsInmostcase,however,thefaultliesinthevasopressin(后叶升压素，即抗利尿素)receptor,whichistypicallyshortenedastheresultofamutationthatintroducesastopcodonintothemRNA,causingprematureterminationofpolypeptidesynthe

6、sis.AdifferenttypeofdebilitatingmutationinthissameGPCRleadstoanaminoacidsubstitutionatthejunctionbetweenthethirdtransmembranesegmentandthesecondintracellularloop.Eventhoughthisreceptorcanstillbindvasopressinatitsexternalsurface,thereceptorcannotactivatetheGproteinandthusca

7、nnotpassthesignaldownstreamtotheeffector.12.3NewdiscoveryinkoreaHermotherandherfatherarenotsufferedfromthisdisease.Thegirl’sdiseasewasthoughttobeanautosomalrecessiveform.Ala(GCC)toAsp(GAC)inexon1inheritedformherfatherandArg(CGC)toHis(CAC)inexon3inheritedfromhermother.