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

Amyotrophic Lateral Sclerosis / genetics Case-Control Studies Exome / genetics Female Genetic Predisposition to Disease / genetics Genetic Variation / genetics Heat-Shock Proteins / genetics Humans Male Molecular Chaperones / genetics

Journal

Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671

Informations de publication

Date de publication:
12 2019
Historique:
received: 16 05 2019
accepted: 02 10 2019
pubmed: 27 11 2019
medline: 1 2 2020
entrez: 27 11 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41593-019-0530-0 PMID: 31768050 PMC: PMC6919277
pubmed: 31768050
doi: 10.1038/s41593-019-0530-0
pii: 10.1038/s41593-019-0530-0
pmc: PMC6919277
mid: NIHMS1061640
doi:

Substances chimiques

DNAJC7 protein, human 0
Heat-Shock Proteins 0
Molecular Chaperones 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1966-1974

Subventions

Organisme : Medical Research Council
ID : MR/L501529/1
Pays : United Kingdom
Organisme : NCATS NIH HHS
ID : U2C TR002818
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS092091
Pays : United States
Organisme : MRF
ID : MRF_MRF-060-0003-RG-SMITH
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100695
Pays : United Kingdom
Organisme : Motor Neurone Disease Association
ID : ALCHALABI-DOBSON/APR14/829-791
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0500289
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Motor Neurone Disease Association
ID : SHAW/NOV14/985-797
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L021803/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900635
Pays : United Kingdom
Organisme : Motor Neurone Disease Association
ID : SMITH/APR16/847-791
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17115
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0600974
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R024804/1
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : U01 MH115727
Pays : United States
Organisme : Medical Research Council
ID : G0900688
Pays : United Kingdom

Commentaires et corrections

Type : ErratumIn

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Auteurs

Sali M K Farhan (SMK)

Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. sfarhan@broadinstitute.org.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. sfarhan@broadinstitute.org.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. sfarhan@broadinstitute.org.
ORCID: 0000-0001-5936-0957

Daniel P Howrigan (DP)

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.
ORCID: 0000-0002-7721-4838

Liam E Abbott (LE)

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.

Joseph R Klim (JR)

Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
ORCID: 0000-0001-8119-2144

Simon D Topp (SD)

United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
ORCID: 0000-0002-5200-3284

Andrea E Byrnes (AE)

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.

Claire Churchhouse (C)

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.

Hemali Phatnani (H)

Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY, USA.

Bradley N Smith (BN)

United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Evadnie Rampersaud (E)

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Gang Wu (G)

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
ORCID: 0000-0002-1678-5864

Joanne Wuu (J)

Department of Neurology, University of Miami, Miami, FL, USA.

Aleksey Shatunov (A)

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.

Alfredo Iacoangeli (A)

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.

Ahmad Al Khleifat (A)

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.

Daniel A Mordes (DA)

Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.

Sulagna Ghosh (S)

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.

Kevin Eggan (K)

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.
ORCID: 0000-0003-4436-8467

Rosa Rademakers (R)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Jacob L McCauley (JL)

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.
ORCID: 0000-0002-1805-1733

Rebecca Schüle (R)

Center for Neurology and Hertie Institute für Clinical Brain Research, University of Tübingen, German Center for Neurodegenerative Diseases, Tübingen, Germany.

Stephan Züchner (S)

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.

Michael Benatar (M)

Department of Neurology, University of Miami, Miami, FL, USA.

J Paul Taylor (JP)

Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Michael Nalls (M)

Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
Data Tecnica International, Glen Echo, MD, USA.

Marc Gotkine (M)

Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Pamela J Shaw (PJ)

Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.

Karen E Morrison (KE)

Faculty of Medicine, University of Southampton and Department of Neurology, University Hospital Southampton, Southampton, UK.

Ammar Al-Chalabi (A)

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
Department of Neurology, King's College Hospital, London, UK.
ORCID: 0000-0002-4924-7712

Bryan Traynor (B)

Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

Christopher E Shaw (CE)

United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Centre for Brain Research, University of Auckland, Auckland, New Zealand.

David B Goldstein (DB)

Institute for Genomic Medicine, Columbia University, New York, NY, USA.
ORCID: 0000-0002-1111-2820

Matthew B Harms (MB)

Department of Neurology, Columbia University, New York, NY, USA.

Mark J Daly (MJ)

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.
ORCID: 0000-0002-0949-8752

Benjamin M Neale (BM)

Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. bneale@broadinstitute.org.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. bneale@broadinstitute.org.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. bneale@broadinstitute.org.
ORCID: 0000-0003-1513-6077

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Classifications MeSH

questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles de l'homéostasie des protéines › Protéinopathies TDP-43 › Sclérose latérale amyotrophique › Exome sequencing in amyotrophic lateral...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Exome sequencing in amyotrophic lateral...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Exome › Exome sequencing in amyotrophic lateral...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Exome sequencing in amyotrophic lateral...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Exome sequencing in amyotrophic lateral...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Chaperons moléculaires › Protéines du choc thermique › Exome sequencing in amyotrophic lateral...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Exome sequencing in amyotrophic lateral...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Chaperons moléculaires › Exome sequencing in amyotrophic lateral...