ArticleNature neuroscience2019
Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein.
Erratum issuedOpen access · greenAbstract read
In one paragraph
Article in Nature neuroscience, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 82 papers.
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82citing papers in PubMed
14.4field-weighted citation impact, top 1% of its field
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Who cites it
82 citing papers in PubMed, 146 citations in OpenAlex.
- Insertion or deletion variants in TAF15 exon 15 are genetic factors impacting the prognosis of amyotrophic lateral sclerosis in a Japanese cohort.European journal of human genetics : EJHG · 2026Article
- Wiring of cellular proteostasis by J-domain proteins.Cell stress & chaperones · 2026Review
- Extracellular Pgk1 or Its Derived Short Peptide Interacted with Membrane-Associated Enolase 2 Receptor: A Potential Therapy for ALS Motor Neuron Degeneration.Biomolecules · 2026Review
- Holding but not folding: How a single charge flip uncouples the DNAJC7-Hsp70 relay in amyotrophic lateral sclerosis.The FEBS journal · 2026Article
- Comprehensive clinical and genetic architecture of familial amyotrophic lateral sclerosis in China: A 15-year cohort study with 302 families.Neural regeneration research · 2026Article
- The ALS-associated E425K mutation uncouples DNAJC7 from the Hsp70 chaperone cycle.The FEBS journal · 2026Article
- The Hsp40 cochaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation.The Journal of biological chemistry · 2026Article
- Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis.Nature genetics · 2026Article
- TDP43 and hnRNP K Regulate Alternative Splicing of DNAJC5.Cell biology international · 2026Article
- Metabolic functions for molecular chaperones and stress proteins in microcephaly.Cellular and molecular life sciences : CMLS · 2025Review
- Entering the era of precision medicine to treat amyotrophic lateral sclerosis.Molecular neurodegeneration · 2025Review
- Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications.Journal of neurology, neurosurgery, and psychiatry · 2025Article
- Biallelic variants in DNAJC7 cause familial amyotrophic lateral sclerosis with the TDP-43 pathology.Acta neuropathologica · 2025Article
- Regulation of physiological and pathological condensates by molecular chaperones.The FEBS journal · 2025Review
- Scouring the human Hsp70 network uncovers diverse chaperone safeguards buffering TDP-43 toxicity.bioRxiv : the preprint server for biology · 2025Article
- Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD.bioRxiv : the preprint server for biology · 2025Article
- Unlocking Disease-Modifying Treatments for TDP-43-Mediated Neurodegeneration.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.Neurology. Genetics · 2025Review
- Red Blood Cell-Related Phenotype-Genotype Correlations in Chronic and Acute Critical Illnesses (Traumatic Brain Injury Cohort and COVID-19 Cohort).International journal of molecular sciences · 2025Article
- Machine learning identified novel players in lipid metabolism, endosomal trafficking, and iron metabolism of the ALS spinal cord.Scientific reports · 2025Article
22 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
39 authors at 15 institutions in 5 countries.
Sali M K FarhanAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. sfarhan@broadinstitute.org.ORCID http://orcid.org/0000-0001-5936-0957
Daniel P HowriganAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-7721-4838
Liam E AbbottAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Joseph R KlimDepartment of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-8119-2144
Simon D ToppUnited Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.ORCID http://orcid.org/0000-0002-5200-3284
Andrea E ByrnesAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Claire ChurchhouseAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Hemali PhatnaniCenter for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY, USA.
Bradley N SmithUnited Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Evadnie RampersaudDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Gang WuDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0002-1678-5864
Joanne WuuDepartment of Neurology, University of Miami, Miami, FL, USA.
Aleksey ShatunovDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
Alfredo IacoangeliDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
Ahmad Al KhleifatDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
Daniel A MordesDepartment of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
Sulagna GhoshStanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
ALSGENS Consortium
FALS Consortium
Project MinE Consortium
CReATe Consortium
Kevin EgganStanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-4436-8467
Rosa RademakersDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Jacob L McCauleyJohn P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.ORCID http://orcid.org/0000-0002-1805-1733
Rebecca SchüleCenter for Neurology and Hertie Institute für Clinical Brain Research, University of Tübingen, German Center for Neurodegenerative Diseases, Tübingen, Germany.
Stephan ZüchnerJohn P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.
Michael BenatarDepartment of Neurology, University of Miami, Miami, FL, USA.
J Paul TaylorHoward Hughes Medical Institute, Chevy Chase, MD, USA.
Michael NallsMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
Marc GotkineDepartment of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Pamela J ShawSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
Karen E MorrisonFaculty of Medicine, University of Southampton and Department of Neurology, University Hospital Southampton, Southampton, UK.
Ammar Al-ChalabiDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.ORCID http://orcid.org/0000-0002-4924-7712
Bryan TraynorMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
Christopher E ShawUnited Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
David B GoldsteinInstitute for Genomic Medicine, Columbia University, New York, NY, USA.ORCID http://orcid.org/0000-0002-1111-2820
Matthew B HarmsDepartment of Neurology, Columbia University, New York, NY, USA.
Mark J DalyAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-0949-8752
Benjamin M NealeAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. bneale@broadinstitute.org.ORCID http://orcid.org/0000-0003-1513-6077
Broad Institute · USKing's College London · GBUniversity of Miami · USSt. Jude Children's Research Hospital · USColumbia University · USHarvard University · USData Tecnica International (United States) · USGerman Center for Neurodegenerative Diseases · DEHadassah Medical Center · ILJohns Hopkins University · USMayo Clinic in Florida · USNew York Genome Center · USUniversity Hospital Southampton NHS Foundation Trust · GBUniversity of Auckland · NZUniversity of Sheffield · GB
Funding
The Impact of COVID-19 on People Living with Rare Diseases and Their FamiliesU2CTR002818 · NCATS · CINCINNATI CHILDRENS HOSP MED CTR · PI Maurizio Macaluso · 2019 to 2026
$51.2MGenetic neuroscience: How human genes and alleles shape neuronal phenotypesU01MH115727 · NIMH · BROAD INSTITUTE, INC. · PI ARLOTTA, PAOLA, BABADI, MEHRTASH · 2017 to 2021
$20.8MUncovering new genes and disease modifiers for ALS and related disordersU54NS092091 · NINDS · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI Michael Benatar · 2014 to 2026
$19.8MMedical Research Council G0500289Medical Research Council G0600974Medical Research Council G0900635Medical Research Council G0900688Medical Research Council G1100695Medical Research Council MC_PC_17115Medical Research Council MR/L021803/1Medical Research Council MR/L501529/1Medical Research Council MR/R024804/1Motor Neurone Disease Association ALCHALABI-DOBSON/APR14/829-791Motor Neurone Disease Association SHAW/NOV14/985-797Motor Neurone Disease Association SMITH/APR16/847-791MRF_ MRF-060-0003-RG-SMITHNCATS NIH HHS U2C TR002818NIMH NIH HHS U01 MH115727NINDS NIH HHS U54 NS092091Wellcome Trust
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.
Indexed as
Amyotrophic Lateral SclerosisCase-Control StudiesExomeFemaleGenetic Predisposition to DiseaseGenetic VariationHeat-Shock ProteinsHumansMaleMolecular ChaperonesDNAJC7 protein, humanHeat-Shock ProteinsMolecular Chaperones
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