A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.,Cell

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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

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia; Genetics of Learning Disability Service, Waratah, NSW 2298, Australia.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Pediatrics, Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany.
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia.
Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia; Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Baylor College of Medicine, Houston, TX 77030, USA.
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Sydney Children's Hospital, Randwick, NSW 2031, Australia.
Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia.
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
GeneDx, 207 Perry Pkwy Gaithersburg, MD 20877, USA.
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.
Sydney Children's Hospital, Randwick, NSW 2031, Australia; Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia; Neuroscience Research Australia and Prince of Wales Clinical School, University of New South Wales, Randwick, NSW 2031, Australia.
Department of Medical Genetics, University of Alberta, AB T6G 2H7, Canada.
Department of Medical Genetics, University of Alberta, AB T6G 2H7, Canada; Departments of Medicine (Neurology) and Pediatrics, University of Alberta, AB, Canada.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.

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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