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Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein.
Farhan, Sali M K; Howrigan, Daniel P; Abbott, Liam E; Klim, Joseph R; Topp, Simon D; Byrnes, Andrea E; Churchhouse, Claire; Phatnani, Hemali; Smith, Bradley N; Rampersaud, Evadnie; Wu, Gang; Wuu, Joanne; Shatunov, Aleksey; Iacoangeli, Alfredo; Al Khleifat, Ahmad; Mordes, Daniel A; Ghosh, Sulagna; Eggan, Kevin; Rademakers, Rosa; McCauley, Jacob L; Schüle, Rebecca; Züchner, Stephan; Benatar, Michael; Taylor, J Paul; Nalls, Michael; Gotkine, Marc; Shaw, Pamela J; Morrison, Karen E; Al-Chalabi, Ammar; Traynor, Bryan; Shaw, Christopher E; Goldstein, David B; Harms, Matthew B; Daly, Mark J; Neale, Benjamin M.
Afiliação
  • Farhan SMK; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. sfarhan@broadinstitute.org.
  • Howrigan DP; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. sfarhan@broadinstitute.org.
  • Abbott LE; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. sfarhan@broadinstitute.org.
  • Klim JR; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Topp SD; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Byrnes AE; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Churchhouse C; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Phatnani H; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Smith BN; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Rampersaud E; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
  • Wu G; United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
  • Wuu J; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Shatunov A; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Iacoangeli A; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Al Khleifat A; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Mordes DA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Ghosh S; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Eggan K; Department of Neurology, University of Miami, Miami, FL, USA.
  • Rademakers R; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
  • McCauley JL; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
  • Schüle R; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
  • Züchner S; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
  • Benatar M; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
  • Taylor JP; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Nalls M; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
  • Traynor B; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Shaw CE; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
  • Goldstein DB; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  • Harms MB; John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.
  • Daly MJ; The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA.
  • Neale BM; Center for Neurology and Hertie Institute für Clinical Brain Research, University of Tübingen, German Center for Neurodegenerative Diseases, Tübingen, Germany.
Nat Neurosci ; 22(12): 1966-1974, 2019 12.
Article em En | MEDLINE | ID: mdl-31768050
ABSTRACT
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Chaperonas Moleculares / Predisposição Genética para Doença / Exoma / Proteínas de Choque Térmico / Esclerose Lateral Amiotrófica Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
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PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Chaperonas Moleculares / Predisposição Genética para Doença / Exoma / Proteínas de Choque Térmico / Esclerose Lateral Amiotrófica Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article