Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia.
Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia.
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DOI：
10.1002/ana.24119
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发表时间：
2014-04
影响因子：
11.2
通讯作者：
Torkamani, Ali
中科院分区：
文献类型：
--
作者：
Chen, Ying-Zhang;Friedman, Jennifer R.;Chen, Dong-Hui;Chan, Guy C. -K.;Bloss, Cinnamon S.;Hisama, Fuki M.;Topol, Sarah E.;Carson, Andrew R.;Pham, Phillip H.;Bonkowski, Emily S.;Scott, Erick R.;Lee, Janel K.;Zhang, Guangfa;Oliveira, Glenn;Xu, Jian;Scott-Van Zeeland, Ashley A.;Chen, Qi;Levy, Samuel;Topol, Eric J.;Storm, Daniel;Swanson, Phillip D.;Bird, Thomas D.;Schork, Nicholas J.;Raskind, Wendy H.;Torkamani, Ali
确定2例不相关的散发病例中儿童期发作的不自主阵发性舞蹈样和张力障碍性运动的原因，并研究腺苷酸环化酶5（ADCY5）错义突变对散发和遗传性常染色体显性遗传家族性运动障碍伴面部肌震颤（FDFM）病例的功能影响。对2个亲子三人组进行全外显子组测序。通过测量刺激和抑制条件下的环磷酸腺苷（cAMP）积累来研究ADCY5突变的影响。在两个研究病例中发现ADCY5中相同的从头突变（c.1252C> T，p.R418W）。在一个FDFM家族中曾报道过ADCY5基因的一个遗传性错义突变（c.2176G> A，p.A726T）。在这两种情况下，只有在发现分子联系后，才能识别与FDFM的显著表型重叠。FDFM家族中的遗传突变和复发性从头突变分别影响不同蛋白质结构域中的残基，第一胞质结构域和第一跨膜结构域。功能研究显示，β受体激动剂刺激的细胞内cAMP在统计学上显著增加，与两种突变体相对于野生型蛋白的腺苷酸环化酶活性增加一致，表明功能获得效应。FDFM可能是由ADCY5不同结构域中的功能获得性突变引起的，ADCY5是腺苷酸环化酶突变与人类疾病之间的第一个明确联系。我们已经阐明了无假设外显子组测序在建立具有复杂和可变表型的罕见疾病诊断中的作用。ADCY5突变应考虑在未确诊的复杂运动障碍患者，即使在没有家族史。
To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM). Whole exome sequencing was performed on 2 parent–child trios. The effect of mutations in ADCY5 was studied by measurement of cyclic adenosine monophosphate (cAMP) accumulation under stimulatory and inhibitory conditions. The same de novo mutation (c.1252C>T, p.R418W) in ADCY5 was found in both studied cases. An inherited missense mutation (c.2176G>A, p.A726T) in ADCY5 was previously reported in a family with FDFM. The significant phenotypic overlap with FDFM was recognized in both cases only after discovery of the molecular link. The inherited mutation in the FDFM family and the recurrent de novo mutation affect residues in different protein domains, the first cytoplasmic domain and the first membrane-spanning domain, respectively. Functional studies revealed a statistically significant increase in β-receptor agonist-stimulated intracellular cAMP consistent with an increase in adenylyl cyclase activity for both mutants relative to wild-type protein, indicative of a gain-of-function effect. FDFM is likely caused by gain-of-function mutations in different domains of ADCY5—the first definitive link between adenylyl cyclase mutation and human disease. We have illustrated the power of hypothesis-free exome sequencing in establishing diagnoses in rare disorders with complex and variable phenotype. Mutations in ADCY5 should be considered in patients with undiagnosed complex movement disorders even in the absence of a family history.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
DOI：
10.1523/jneurosci.3985-08.2009
发表时间：
2009-01-07
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen Q;Peto CA;Shelton GD;Mizisin A;Sawchenko PE;Schubert D
通讯作者：
Schubert D
影响因子：
56.9
作者：
Bailey, JA;Gu, ZP;Eichler, EE
通讯作者：
Eichler, EE
影响因子：
4
作者：
BIRD, TD;CARLSON, CB;HALL, JG
通讯作者：
HALL, JG