外显子组捕获显示ZNF423和CEP164突变,肾ciliopathies与DNA损伤反应信号。
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Chaki M, Airik R, Ghosh AK,贾尔斯RH,陈R, Slaats GG,王H,赫德TW,周W, Cluckey,哇,为什么Ramaswami G,香港CJ,汉密尔顿英航,Cervenka我Ganji RS, Bryja V,艺术HH, van Reeuwijk J,乌得琴MM, Letteboer SJ, Roepman R,小量H, Ibraghimov-Beskrovnaya O, Yasunaga T, Walz G,等L,说话是的,蔽护所B, Liebau MC,奔驰T, Le来往,德拉蒙德我,詹森,艾伦SJ, Natarajan年代,O ' toole摩根富林明,Attanasio M, Saunier年代,Antignac C, Koenekoop RK,任H,洛佩兹,Nayir, Stoetzel C, Dollfus H,马苏迪R,格里森詹,安德烈奥利SP, Doherty DG, Lindstrad, Golzio C, Katsanis N,佩普L, Abboud EB, Al-Rajhi AA,刘易斯RA,奥木兰·H,李EY、王年代,Sekiguchi JM,桑德斯R,约翰逊CA,加纳E, Vanselow K,安徒生JS, Shlomai J,纽伦堡G,纽伦堡P,利维年代,Smogorzewska,奥托EA, Hildebrandt F
外显子组捕获显示ZNF423和CEP164突变,肾ciliopathies与DNA损伤反应信号。
细胞。2012年8月3日,150 (3):533 - 48。doi: 10.1016 / j.cell.2012.06.028。
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22863007 (在PubMed]
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Nephronophthisis-related ciliopathies (NPHP-RC)退行性隐性疾病,影响肾、视网膜和大脑。NPHP基因的遗传缺陷产品本地化和纤毛中心体将他们定义为“ciliopathies。”However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR.