Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.
Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.
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DOI：
10.1056/nejmoa1609009
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发表时间：
2017-02-23
期刊：
影响因子：
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通讯作者：
Sanna-Cherchi S
中科院分区：
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作者：
Lopez-Rivera E;Liu YP;Verbitsky M;Anderson BR;Capone VP;Otto EA;Yan Z;Mitrotti A;Martino J;Steers NJ;Fasel DA;Vukojevic K;Deng R;Racedo SE;Liu Q;Werth M;Westland R;Vivante A;Makar GS;Bodria M;Sampson MG;Gillies CE;Vega-Warner V;Maiorana M;Petrey DS;Honig B;Lozanovski VJ;Salomon R;Heidet L;Carpentier W;Gaillard D;Carrea A;Gesualdo L;Cusi D;Izzi C;Scolari F;van Wijk JA;Arapovic A;Saraga-Babic M;Saraga M;Kunac N;Samii A;McDonald-McGinn DM;Crowley TB;Zackai EH;Drozdz D;Miklaszewska M;Tkaczyk M;Sikora P;Szczepanska M;Mizerska-Wasiak M;Krzemien G;Szmigielska A;Zaniew M;Darlow JM;Puri P;Barton D;Casolari E;Furth SL;Warady BA;Gucev Z;Hakonarson H;Flogelova H;Tasic V;Latos-Bielenska A;Materna-Kiryluk A;Allegri L;Wong CS;Drummond IA;D'Agati V;Imamoto A;Barasch JM;Hildebrandt F;Kiryluk K;Lifton RP;Morrow BE;Jeanpierre C;Papaioannou VE;Ghiggeri GM;Gharavi AG;Katsanis N;Sanna-Cherchi S
DiGeorge综合征是最常见的微缺失综合征，影响多个器官，包括心脏，神经系统和肾脏。它是由染色体22q11.2上的缺失引起的;肾脏缺陷的遗传驱动因素尚不清楚。我们在两个队列中进行了全基因组结构变异搜索：2080例先天性肾脏和尿路畸形患者和22,094例对照。我们对另外586例先天性肾脏畸形患者的样本进行了外显子组和靶向重测序。我们还使用斑马鱼和小鼠进行了功能研究。我们在1.1%的先天性肾脏畸形患者和0.01%的对照人群中发现了22q11.2的杂合缺失（比值比，81.5; P=4.5×10−14）。我们将DiGeorge综合征中肾脏疾病的主要驱动因素定位于包含9个基因的370 kb区域。在斑马鱼胚胎中，snap 29、aifm 3和crkl的功能被诱导丧失导致肾缺陷; crkl单独丧失就足以诱导缺陷。586例先天性泌尿系统异常患者中有5例在CRKL中发现了新的杂合蛋白改变变体，包括提前终止密码子。在小鼠模型中Crkl的失活诱导了与在患有先天性泌尿系统异常的患者中观察到的发育缺陷相似的发育缺陷。我们确定了一个经常性的370 kb的缺失在22 q11.2基因座作为驱动器的DiGeorge综合征和散发性先天性肾脏和泌尿道异常的肾脏缺陷。在该基因座的9个基因中，SNAP 29、AIFM 3和CRKL似乎对表型至关重要，CRKL的单倍不足成为主要的遗传驱动因素。（由美国国立卫生研究院和其他机构资助。
The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10−14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)