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Rare Variant Burden Analysis within Enhancers Identifies CAV1 as a New ALS Risk Gene

38 Pages Posted: 11 Jun 2020 Publication Status: Review Complete

See all articles by Johnathan Cooper-Knock

Johnathan Cooper-Knock

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Sai Zhang

Stanford University - Stanford Center for Genomics and Personalized Medicine

Kevin P. Kenna

University of Massachusetts Worcester - Department of Neurology

Tobias Moll

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

John Franklin

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Samantha Allen

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Helia Ghahremani Nezhad

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Nancy S. Yacovzada

Weizmann Institute of Science - Department of Molecular Genetics

Chen Eitan

Weizmann Institute of Science - Department of Molecular Genetics

Eran Hornstein

Weizmann Institute of Science - Department of Molecular Genetics

Eran Ehilak

Lund University - Department of Biology

Petra Celadova

University of Sheffield - Sheffield Institute for Nucleic Acids (SInFoNiA)

Daniel Bose

University of Sheffield - Sheffield Institute for Nucleic Acids (SInFoNiA)

Sali MK Farhan

Massachusetts General Hospital and Harvard Medical School - Analytic and Translational Genetics Unit

Simon Fishilevich

Weizmann Institute of Science - Department of Molecular Genetics

Doron Lancet

Weizmann Institute of Science - Department of Molecular Genetics

Karen E. Morrison

University of Southampton - Faculty of Medicine, Health and Life Sciences

Chris Shaw

University of London - Maurice Wohl Clinical Neuroscience Institute

Ammar Al-Chalabi

King’s College London - Institute of Psychiatry, Psychology and Neuroscience

Project MinE ALS Sequencing Consortium

Jan H. Veldink

Utrecht University - Department of Neurology

Janine Kirby

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Michael P. Snyder

Stanford University - Stanford Center for Genomics and Personalized Medicine

Pamela J. Shaw

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

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Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organise membrane lipid rafts (MLR) important for cell signalling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localise a large proportion of ALS-risk variants within the non-coding genome, but further characterisation has been limited by lack of appropriate tools.  Applying a new pipeline to identify pathogenic genetic variation within enhancer-elements responsible for regulating gene expression, we have discovered disease-associated variation within CAV1/CAV2 enhancers, which replicated in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLR in patient-derived cells; and CRISPR/Cas9 perturbation proximate to a patient-mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as a new ALS gene. We propose CAV1/CAV2 overexpression as a personalised medicine target for ALS.

Keywords: Amyotrophic lateral sclerosis, whole genome sequencing, CAV1, CAV2, noncoding DNA

Suggested Citation

Cooper-Knock, Johnathan and Zhang, Sai and Kenna, Kevin P. and Moll, Tobias and Franklin, John and Allen, Samantha and Nezhad, Helia Ghahremani and Yacovzada, Nancy S. and Eitan, Chen and Hornstein, Eran and Ehilak, Eran and Celadova, Petra and Bose, Daniel and Farhan, Sali MK and Fishilevich, Simon and Lancet, Doron and Morrison, Karen E. and Shaw, Chris and Al-Chalabi, Ammar and Sequencing Consortium, Project MinE ALS and Veldink, Jan H. and Kirby, Janine and Snyder, Michael P. and Shaw, Pamela J., Rare Variant Burden Analysis within Enhancers Identifies CAV1 as a New ALS Risk Gene. Available at SSRN: https://ssrn.com/abstract=3606796 or http://dx.doi.org/10.2139/ssrn.3606796
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Johnathan Cooper-Knock (Contact Author)

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN) ( email )

385a Glossop Road
Sheffield
United Kingdom

Sai Zhang

Stanford University - Stanford Center for Genomics and Personalized Medicine

Stanford, CA 94305
United States

Kevin P. Kenna

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

Tobias Moll

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN) ( email )

385a Glossop Road
Sheffield
United Kingdom

John Franklin

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Samantha Allen

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Helia Ghahremani Nezhad

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN) ( email )

385a Glossop Road
Sheffield
United Kingdom

Nancy S. Yacovzada

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Chen Eitan

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Eran Hornstein

Weizmann Institute of Science - Department of Molecular Genetics

Rehovot, 7610001
Israel

Eran Ehilak

Lund University - Department of Biology ( email )

Box 117
Lund, S221 00
Sweden

Petra Celadova

University of Sheffield - Sheffield Institute for Nucleic Acids (SInFoNiA) ( email )

United Kingdom

Daniel Bose

University of Sheffield - Sheffield Institute for Nucleic Acids (SInFoNiA) ( email )

United Kingdom

Sali MK Farhan

Massachusetts General Hospital and Harvard Medical School - Analytic and Translational Genetics Unit ( email )

Boston, MA
United States

Simon Fishilevich

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Doron Lancet

Weizmann Institute of Science - Department of Molecular Genetics ( email )

Rehovot, 7610001
Israel

Karen E. Morrison

University of Southampton - Faculty of Medicine, Health and Life Sciences

Southampton
United Kingdom

Chris Shaw

University of London - Maurice Wohl Clinical Neuroscience Institute ( email )

Strand
London, England WC2R 2LS
United Kingdom

Ammar Al-Chalabi

King’s College London - Institute of Psychiatry, Psychology and Neuroscience

London
United Kingdom

Jan H. Veldink

Utrecht University - Department of Neurology

GA Utrecht
Netherlands

Janine Kirby

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

Michael P. Snyder

Stanford University - Stanford Center for Genomics and Personalized Medicine

Stanford, CA 94305
United States

Pamela J. Shaw

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

385a Glossop Road
Sheffield
United Kingdom

No contact information is available for Project MinE ALS Sequencing Consortium

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