Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome
Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome
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DOI：
10.1016/j.ajhg.2018.07.010
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发表时间：
2018-09-06
影响因子：
9.8
通讯作者：
Gleeson, Joseph G.
中科院分区：
文献类型：
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作者：
Ghosh, Shereen G.;Becker, Kerstin;Gleeson, Joseph G.
ADP-核糖基化，将聚ADP核糖（PAR）添加到蛋白质上，是对细胞挑战（如兴奋性毒性或氧化应激）的响应信号。该过程由一组称为聚（ADP-核糖）聚合酶（PARP）的酶催化。由于具有这种修饰的蛋白质的积累导致细胞死亡，因此其负调节恢复细胞内稳态：这是由聚ADP核糖糖水解酶（PARG）和ADP-核糖水解酶蛋白（ARH）介导的过程。利用连锁分析和外显子组或基因组测序，我们确定了ADPRHL 2的隐性失活突变在6个家庭。受影响的个体表现出一种儿科发病的神经退行性疾病，伴有进行性脑萎缩、发育退化和癫痫发作，与应激期（如感染）相关。果蝇Parg基因的缺失对人ADPRHL 2所拯救的氧化攻击具有致死性，表明其功能保守。PARP的药理学抑制也挽救了表型，表明这种遗传疾病的出生后治疗的可能性。
ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.