Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein
| Autor: | Alfredo Iacoangeli, Simon Topp, Benjamin M. Neale, Kevin Eggan, Pamela J. Shaw, Ahmad Al Khleifat, Andrea Byrnes, Sulagna Ghosh, Ammar Al-Chalabi, Bryan J. Traynor, Karen E. Morrison, Marc Gotkine, Rosa Rademakers, David Goldstein, Mike A. Nalls, Michael Benatar, Rebecca Schüle, Evadnie Rampersaud, Claire Churchhouse, Joanne Wuu, Sali M.K. Farhan, Aleksey Shatunov, Stephan Züchner, J. Paul Taylor, Liam Abbott, Christopher Shaw, Daniel P. Howrigan, Mark J. Daly, Jacob L. McCauley, Hemali Phatnani, Gang Wu, Joseph R. Klim, Daniel A. Mordes, Bradley N. Smith, Matthew B. Harms |
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| Přispěvatelé: | ALSGENS Consortium, FALS Consortium, Project MinE Consortium, CReATe Consortium |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Protein family SOD1 Protein aggregation Biology Article 03 medical and health sciences 0302 clinical medicine genetics [Heat-Shock Proteins] genetics [Molecular Chaperones] Heat shock protein ddc:570 DNAJC7 protein human medicine genetics [Exome] Humans Exome Genetic Predisposition to Disease Amyotrophic lateral sclerosis genetics [Genetic Predisposition to Disease] Gene Exome sequencing Heat-Shock Proteins Genetics General Neuroscience Neurodegeneration Amyotrophic Lateral Sclerosis Genetic Variation medicine.disease genetics [Genetic Variation] genetics [Amyotrophic Lateral Sclerosis] 030104 developmental biology Case-Control Studies Female Human medicine Neuroscience 030217 neurology & neurosurgery Molecular Chaperones |
| Zdroj: | Nature neuroscience Nature reviews / Neuroscience 22(12), 1966-1974 (2019). doi:10.1038/s41593-019-0530-0 |
| ISSN: | 1097-6256 |
| DOI: | 10.1038/s41593-019-0530-0 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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