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

Sali M K Farhan; Daniel P Howrigan; Liam E Abbott; Joseph R Klim; Simon D Topp; Andrea E Byrnes; Claire Churchhouse; Hemali Phatnani; Bradley N Smith; Evadnie Rampersaud; Gang Wu; Joanne Wuu; Aleksey Shatunov; Alfredo Iacoangeli; Ahmad Al Khleifat; Daniel A Mordes; Sulagna Ghosh; ALSGENS Consortium; FALS Consortium; Project MinE Consortium; CReATe Consortium; Kevin Eggan; Rosa Rademakers; Jacob L McCauley; Rebecca Schüle; Stephan Züchner; Michael Benatar; J Paul Taylor; Michael Nalls; Marc Gotkine; Pamela J Shaw; Karen E Morrison; Ammar Al-Chalabi; Bryan Traynor; Christopher E Shaw; David B Goldstein; Matthew B Harms; Mark J Daly; Benjamin M Neale

doi:10.1038/s41593-019-0530-0

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

Nat Neurosci. 2019 Dec;22(12):1966-1974. doi: 10.1038/s41593-019-0530-0. Epub 2019 Nov 25.

Authors

Sali M K Farhan^{1

2

3}, Daniel P Howrigan^{4

5

6}, Liam E Abbott^{4

5

6}, Joseph R Klim⁷, Simon D Topp⁸, Andrea E Byrnes^{4

5

6}, Claire Churchhouse^{4

5

6}, Hemali Phatnani⁹, Bradley N Smith⁸, Evadnie Rampersaud¹⁰, Gang Wu¹⁰, Joanne Wuu¹¹, Aleksey Shatunov¹², Alfredo Iacoangeli^{12

13}, Ahmad Al Khleifat¹², Daniel A Mordes⁷, Sulagna Ghosh^{6

7}; ALSGENS Consortium; FALS Consortium; Project MinE Consortium; CReATe Consortium; Kevin Eggan^{6

7}, Rosa Rademakers¹⁴, Jacob L McCauley^{15

16}, Rebecca Schüle¹⁷, Stephan Züchner^{15

16}, Michael Benatar¹¹, J Paul Taylor^{18

19}, Michael Nalls^{20

21}, Marc Gotkine²², Pamela J Shaw²³, Karen E Morrison²⁴, Ammar Al-Chalabi^{12

25}, Bryan Traynor^{20

26}, Christopher E Shaw^{8

27}, David B Goldstein²⁸, Matthew B Harms²⁹, Mark J Daly^{4

5

6}, Benjamin M Neale^{30

31

32}

Affiliations

¹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. sfarhan@broadinstitute.org.
² Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. sfarhan@broadinstitute.org.
³ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. sfarhan@broadinstitute.org.
⁴ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁶ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁷ Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
⁸ United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁹ Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY, USA.
¹⁰ Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹¹ Department of Neurology, University of Miami, Miami, FL, USA.
¹² Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
¹³ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹⁴ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
¹⁵ John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.
¹⁶ The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA.
¹⁷ Center for Neurology and Hertie Institute für Clinical Brain Research, University of Tübingen, German Center for Neurodegenerative Diseases, Tübingen, Germany.
¹⁸ Howard Hughes Medical Institute, Chevy Chase, MD, USA.
¹⁹ Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
²⁰ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
²¹ Data Tecnica International, Glen Echo, MD, USA.
²² Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
²³ Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
²⁴ Faculty of Medicine, University of Southampton and Department of Neurology, University Hospital Southampton, Southampton, UK.
²⁵ Department of Neurology, King's College Hospital, London, UK.
²⁶ Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
²⁷ Centre for Brain Research, University of Auckland, Auckland, New Zealand.
²⁸ Institute for Genomic Medicine, Columbia University, New York, NY, USA.
²⁹ Department of Neurology, Columbia University, New York, NY, USA.
³⁰ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. bneale@broadinstitute.org.
³¹ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. bneale@broadinstitute.org.
³² Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. bneale@broadinstitute.org.

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.

Publication types

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

MeSH terms

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*

Substances

DNAJC7 protein, human
Heat-Shock Proteins
Molecular Chaperones

Abstract

Publication types

MeSH terms

Substances

Grants and funding