Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein.,Nature Neuroscience

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Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein.
Nature Neuroscience ( IF 21.2 ) Pub Date : 2019-11-25 , DOI: 10.1038/s41593-019-0530-0
Sali M K Farhan _{1,

2,

3} , Daniel P Howrigan _{1,

2,

3} , Liam E Abbott _{1,

2,

3} , Joseph R Klim ₄ , Simon D Topp ₅ , Andrea E Byrnes _{1,

2,

3} , Claire Churchhouse _{1,

2,

3} , Hemali Phatnani ₆ , Bradley N Smith ₅ , Evadnie Rampersaud ₇ , Gang Wu ₇ , Joanne Wuu ₈ , Aleksey Shatunov ₉ , Alfredo Iacoangeli _{9,

10} , Ahmad Al Khleifat ₉ , Daniel A Mordes ₄ , Sulagna Ghosh _{3,

4} , , , , , Kevin Eggan _{3,

4} , Rosa Rademakers ₁₁ , Jacob L McCauley _{12,

13} , Rebecca Schüle ₁₄ , Stephan Züchner _{12,

13} , Michael Benatar ₈ , J Paul Taylor _{15,

16} , Michael Nalls _{17,

18} , Marc Gotkine ₁₉ , Pamela J Shaw ₂₀ , Karen E Morrison ₂₁ , Ammar Al-Chalabi _{9,

22} , Bryan Traynor _{17,

23} , Christopher E Shaw _{5,

24} , David B Goldstein ₂₅ , Matthew B Harms ₂₆ , Mark J Daly _{1,

2,

3} , Benjamin M Neale _{1,

2,

3}

Affiliation

Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY, USA.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Neurology, University of Miami, Miami, FL, USA.
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.
The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA.
Center for Neurology and Hertie Institute für Clinical Brain Research, University of Tübingen, German Center for Neurodegenerative Diseases, Tübingen, Germany.
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
Data Tecnica International, Glen Echo, MD, USA.
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
Faculty of Medicine, University of Southampton and Department of Neurology, University Hospital Southampton, Southampton, UK.
Department of Neurology, King's College Hospital, London, UK.
Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Centre for Brain Research, University of Auckland, Auckland, New Zealand.
Institute for Genomic Medicine, Columbia University, New York, NY, USA.
Department of Neurology, Columbia University, New York, NY, USA.

To discover novel genes underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry-matched controls. We observed a significant excess of rare protein-truncating variants among ALS cases, and these variants were concentrated in constrained genes. Through gene level analyses, we replicated known ALS genes including SOD1, NEK1 and FUS. We also observed multiple distinct protein-truncating variants in a highly constrained gene, DNAJC7. The signal in DNAJC7 exceeded genome-wide significance, and immunoblotting assays showed depletion of DNAJC7 protein in fibroblasts in a patient with ALS carrying the p.Arg156Ter variant. DNAJC7 encodes a member of the heat-shock protein family, HSP40, which, along with HSP70 proteins, facilitates protein homeostasis, including folding of newly synthesized polypeptides and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of aberrant proteins can occur and lead to protein aggregation, which is a pathological hallmark of neurodegeneration. Our results highlight DNAJC7 as a novel gene for ALS.

中文翻译：

肌萎缩侧索硬化症的外显子组测序暗示了一种新基因 DNAJC7，它编码热休克蛋白。

为了发现肌萎缩侧索硬化症 (ALS) 的新基因，我们汇总了 3,864 例病例和 7,839 例血统匹配对照的外显子组。我们观察到 ALS 病例中存在大量的罕见蛋白质截短变异，并且这些变异集中在受限基因中。通过基因水平分析，我们复制了已知的 ALS 基因，包括 SOD1、NEK1 和 FUS。我们还在高度受限的基因 DNAJC7 中观察到多种不同的蛋白质截短变体。DNAJC7 中的信号超出了全基因组范围的意义，免疫印迹分析显示携带 p.Arg156Ter 变体的 ALS 患者的成纤维细胞中 DNAJC7 蛋白被耗尽。DNAJC7 编码热休克蛋白家族的成员 HSP40，它与 HSP70 蛋白一起促进蛋白质稳态，包括新合成多肽的折叠和降解蛋白质的清除。当这些过程不受调节时，可能会发生异常蛋白质的错误折叠和积累并导致蛋白质聚集，这是神经退行性变的病理标志。我们的结果强调 DNAJC7 是 ALS 的一个新基因。

更新日期：2019-11-26

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