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A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.
Cell ( IF 45.5 ) Pub Date : 2018-Feb-22 , DOI: 10.1016/j.cell.2018.02.006
Vincenzo A Gennarino 1 , Elizabeth E Palmer 2 , Laura M McDonell 3 , Li Wang 1 , Carolyn J Adamski 4 , Amanda Koire 5 , Lauren See 6 , Chun-An Chen 1 , Christian P Schaaf 1 , Jill A Rosenfeld 6 , Jessica A Panzer 7 , Ute Moog 8 , Shuang Hao 9 , Ann Bye 10 , Edwin P Kirk 11 , Pawel Stankiewicz 12 , Amy M Breman 12 , Arran McBride 3 , Tejaswi Kandula 10 , Holly A Dubbs 13 , Rebecca Macintosh 14 , Michael Cardamone 10 , Ying Zhu 15 , Kevin Ying 16 , Kerith-Rae Dias 16 , Megan T Cho 17 , Lindsay B Henderson 17 , Berivan Baskin 17 , Paula Morris 16 , Jiang Tao 18 , Mark J Cowley 18 , Marcel E Dinger 18 , Tony Roscioli 19 , Oana Caluseriu 20 , Oksana Suchowersky 21 , Rani K Sachdev 10 , Olivier Lichtarge 6 , Jianrong Tang 9 , Kym M Boycott 3 , J Lloyd Holder 9 , Huda Y Zoghbi 22
Affiliation  

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.

中文翻译:

轻度 PUM1 突变与成人发病的共济失调有关,而单倍体不足会导致发育迟缓和癫痫发作。

某些突变会导致蛋白质在神经元中积累,从而导致神经退行性变。然而,我们最近表明,由其阻遏物 RNA 结合蛋白 Pumilio1 (PUM1) 的单倍体不足引起的野生型蛋白 Ataxin1 的上调也会导致小鼠神经退行性变。因此,我们搜索了具有 PUM1 突变的人类患者。我们确定了 11 名患有 PUM1 缺失或从头错义变异的个体,他们患有发育综合征(Pumilio1 相关发育障碍、共济失调和癫痫发作;PADDAS)。我们还在一个具有不完全外显率的成年发作性共济失调(Pumilio1-related cerebellar ataxia,PRCA)家族中发现了一种较轻微的错义突变。对患者来源细胞的研究表明,错义突变使 PUM1 蛋白水平在成人发病病例中降低了 25%,在婴儿发病病例中降低了 50%。已知 PUM1 目标的水平相应增加。因此,蛋白质水平的变化与表型严重程度有关,识别蛋白质表达的转录后调节剂应识别新的候选疾病基因。
更新日期:2018-02-22
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