Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

Irit Reichenstein; Chen Eitan; Sandra Diaz-Garcia; Guy Haim; Iddo Magen; Aviad Siany; Mariah L. Hoye; Natali Rivkin; Tsviya Olender; Beata Toth; Revital Ravid; Amitai D. Mandelbaum; Eran Yanowski; Jing Liang; Jeffrey K. Rymer; Rivka Levy; Gilad Beck; Elena Ainbinder; Sali M. K. Farhan; Kimberly A. Lennox; Nicole M. Bode; Mark A. Behlke; Thomas Möller; Smita Saxena; Cristiane A. M. Moreno; Giancarlo Costaguta; Kristel R. van Eijk; Hemali Phatnani; Ammar Al-Chalabi; A. Nazli Başak; Leonard H. van den Berg; Orla Hardiman; John E. Landers; Jesus S. Mora; Karen E. Morrison; Pamela J. Shaw; Jan H. Veldink; Samuel L. Pfaff; Ofer Yizhar; Christina Gross; Robert H. Brown; John M. Ravits; Matthew B. Harms; Timothy M. Miller; Eran Hornstein

doi:10.1126/scitranslmed.aav5264

Research ArticleAmyotrophic Lateral Sclerosis

Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

Irit Reichenstein¹,*,
Chen Eitan¹,²,*,
Sandra Diaz-Garcia³,
Guy Haim¹,
Iddo Magen¹,
Aviad Siany¹,
Mariah L. Hoye ⁴,
Natali Rivkin¹,
Tsviya Olender¹,
Beata Toth¹,
Revital Ravid¹,
Amitai D. Mandelbaum¹,
Eran Yanowski¹,
Jing Liang¹,
Jeffrey K. Rymer⁵,⁶,
Rivka Levy⁷,
Gilad Beck⁸,
Elena Ainbinder⁸,
Sali M. K. Farhan⁹,¹⁰,
Kimberly A. Lennox¹¹,
Nicole M. Bode¹¹,
Mark A. Behlke¹¹,
Thomas Möller¹²,
Smita Saxena¹³,¹⁴,
Cristiane A. M. Moreno¹⁵,
Giancarlo Costaguta¹⁶,
Kristel R. van Eijk²,¹⁷,
Hemali Phatnani¹⁸,
Ammar Al-Chalabi²,¹⁹,²⁰,
A. Nazli Başak²,²¹,
Leonard H. van den Berg²,¹⁷,
Orla Hardiman²,²²,²³,
John E. Landers²,²⁴,
Jesus S. Mora²,²⁵,
Karen E. Morrison²,²⁶,
Pamela J. Shaw²,²⁷,
Jan H. Veldink²,¹⁷,
Samuel L. Pfaff¹⁶,
Ofer Yizhar⁷,
Christina Gross⁵,⁶,
Robert H. Brown Jr.²⁸,
John M. Ravits³,
Matthew B. Harms¹⁵,
Timothy M. Miller⁴ and
Eran Hornstein ¹,²,†

¹Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
²Project MinE ALS Sequencing Consortium.
³Department of Neurosciences, UC San Diego, La Jolla, CA 92093, USA.
⁴Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁵Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
⁶Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
⁷Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel.
⁸Stem Cell Core and Advanced Cell Technologies Unit, Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel.
⁹Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹⁰Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹¹Integrated DNA Technologies, 1710 Commercial Park, Coralville, IA 52241, USA.
¹²Department of Neurology, School of Medicine, University of Washington, Seattle, WA 98195, USA.
¹³Department of Neurology, Inselspital University Hospital, University of Bern, Freiburgstrasse 16, CH-3010 Bern, Bern, Switzerland.
¹⁴Department for BioMedical Research, University of Bern, Murtenstrasse 40, CH-3008 Bern, Switzerland.
¹⁵Department of Neurology, Columbia University, New York, NY 10032, USA.
¹⁶Gene Expression Laboratory and the Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
¹⁷Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.
¹⁸Center for Genomics of Neurodegenerative Disease (CGND) and New York Genome Center (NYGC) ALS Consortium, New York, NY 10013, USA.
¹⁹Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, Department of Basic and Clinical Neuroscience, Department of Neurology, King’s College London, London SE5 9RX, UK.
²⁰Department of Neurology, King’s College Hospital, London SE5 9RS, UK.
²¹Koç University Translational Medicine Research Center, NDAL, Istanbul 34010, Turkey.
²²Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin 2, Republic of Ireland.
²³Department of Neurology, Beaumont Hospital, Dublin 2, Republic of Ireland.
²⁴Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
²⁵ALS Unit, Hospital San Rafael, Madrid 28016, Spain.
²⁶Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
²⁷Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK.
²⁸Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

↵†Corresponding author. Email: eran.hornstein{at}weizmann.ac.il

↵* These authors contributed equally to this work.

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Science Translational Medicine 18 Dec 2019:
Vol. 11, Issue 523, eaav5264
DOI: 10.1126/scitranslmed.aav5264

Irit Reichenstein

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Chen Eitan

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

Project MinE ALS Sequencing Consortium.

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Sandra Diaz-Garcia

Department of Neurosciences, UC San Diego, La Jolla, CA 92093, USA.

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Guy Haim

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Iddo Magen

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Aviad Siany

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Mariah L. Hoye

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.

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Natali Rivkin

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Tsviya Olender

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Beata Toth

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Revital Ravid

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Amitai D. Mandelbaum

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Eran Yanowski

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Jing Liang

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Jeffrey K. Rymer

Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.

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Rivka Levy

Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Gilad Beck

Stem Cell Core and Advanced Cell Technologies Unit, Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Elena Ainbinder

Stem Cell Core and Advanced Cell Technologies Unit, Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Sali M. K. Farhan

Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

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Kimberly A. Lennox

Integrated DNA Technologies, 1710 Commercial Park, Coralville, IA 52241, USA.

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Nicole M. Bode

Integrated DNA Technologies, 1710 Commercial Park, Coralville, IA 52241, USA.

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Mark A. Behlke

Integrated DNA Technologies, 1710 Commercial Park, Coralville, IA 52241, USA.

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Thomas Möller

Department of Neurology, School of Medicine, University of Washington, Seattle, WA 98195, USA.

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Smita Saxena

Department of Neurology, Inselspital University Hospital, University of Bern, Freiburgstrasse 16, CH-3010 Bern, Bern, Switzerland.

Department for BioMedical Research, University of Bern, Murtenstrasse 40, CH-3008 Bern, Switzerland.

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Cristiane A. M. Moreno

Department of Neurology, Columbia University, New York, NY 10032, USA.

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Giancarlo Costaguta

Gene Expression Laboratory and the Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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Kristel R. van Eijk

Project MinE ALS Sequencing Consortium.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.

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Hemali Phatnani

Center for Genomics of Neurodegenerative Disease (CGND) and New York Genome Center (NYGC) ALS Consortium, New York, NY 10013, USA.

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Ammar Al-Chalabi

Project MinE ALS Sequencing Consortium.

Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, Department of Basic and Clinical Neuroscience, Department of Neurology, King’s College London, London SE5 9RX, UK.

Department of Neurology, King’s College Hospital, London SE5 9RS, UK.

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A. Nazli Başak

Project MinE ALS Sequencing Consortium.

Koç University Translational Medicine Research Center, NDAL, Istanbul 34010, Turkey.

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Leonard H. van den Berg

Project MinE ALS Sequencing Consortium.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.

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Orla Hardiman

Project MinE ALS Sequencing Consortium.

Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin 2, Republic of Ireland.

Department of Neurology, Beaumont Hospital, Dublin 2, Republic of Ireland.

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John E. Landers

Project MinE ALS Sequencing Consortium.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

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Jesus S. Mora

Project MinE ALS Sequencing Consortium.

ALS Unit, Hospital San Rafael, Madrid 28016, Spain.

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Karen E. Morrison

Project MinE ALS Sequencing Consortium.

Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.

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Pamela J. Shaw

Project MinE ALS Sequencing Consortium.

Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK.

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Jan H. Veldink

Project MinE ALS Sequencing Consortium.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.

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Samuel L. Pfaff

Gene Expression Laboratory and the Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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Ofer Yizhar

Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel.

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Christina Gross

Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.

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Robert H. Brown Jr.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

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John M. Ravits

Department of Neurosciences, UC San Diego, La Jolla, CA 92093, USA.

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Matthew B. Harms

Department of Neurology, Columbia University, New York, NY 10032, USA.

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Timothy M. Miller

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.

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Eran Hornstein

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

Project MinE ALS Sequencing Consortium.

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For correspondence: eran.hornstein@weizmann.ac.il

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Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

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