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Mutations in the Sphingolipid Pathway Gene SPTLC1 are a Cause of Amyotrophic Lateral Sclerosis

85 Pages Posted: 6 Jun 2019 Sneak Peek Status: Review Complete

See all articles by Johnson O. Janel

Johnson O. Janel

National Institutes of Health - Neuromuscular Diseases Research Section

Ruth Chia

National Institutes of Health - Neuromuscular Diseases Research Section

Ravindran Kumaran

National Institutes of Health (NIH)

Nada Alahmady

University of London - Maurice Wohl Clinical Neuroscience Institute

Yevgeniya Abramzon

National Institutes of Health - Neuromuscular Diseases Research Section

Faraz Faghri

National Institutes of Health - Molecular Genetics Section

Alan Renton

National Institutes of Health - Neuromuscular Diseases Research Section

Simon D. Topp

United Kingdom Dementia Research Institute Centre

Hannah A. Pliner

National Institutes of Health - Neurodegenerative Diseases Research Unit

J. Raphael Gibbs

National Institutes of Health - Computational Biology Core

Jinhui Ding

National Institutes of Health - Computational Biology Core

Nathan Smith

National Institutes of Health

Natalie Landeck

National Institutes of Health (NIH)

Michael A. Nalls

National Institutes of Health - Laboratory of Neurogenetics

Mark R. Cookson

National Institutes of Health (NIH)

Olga Pletnikova

Johns Hopkins University - School of Medicine

Juan Troncoso

Johns Hopkins University - Department of Pathology

Sonja W. Scholz

National Institutes of Health - Neurodegenerative Diseases Research Unit

Marya S. Sabir

National Institutes of Health - Neurodegenerative Diseases Research Unit

Sarah Ahmed

National Institutes of Health - Neurodegenerative Diseases Research Unit

Clifton L. Dalgard

Uniformed Services University of the Health Sciences

Claire Troakes

United Kingdom Dementia Research Institute Centre

Ashley R. Jones

University of London - Maurice Wohl Clinical Neuroscience Institute

Aleksey Shatunov

University of London - Maurice Wohl Clinical Neuroscience Institute

Alfredo Iacoangeli

University of London - Maurice Wohl Clinical Neuroscience Institute

Ahmad Al Khleifat

University of London - Maurice Wohl Clinical Neuroscience Institute

Nicola Ticozzi

University of Milan - Department of Neurology and Laboratory of Neuroscience

Vincenzo Silani

University of Massachusetts Worcester - Department of Neurology

Cinzia Gellera

Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ - Unit of Genetics of Neurodegenerative and Metabolic Diseases

Ian P. Blair

Macquarie University - Centre for MND Research

Carol Dobson-Stone

University of New South Wales (UNSW) - School of Medical Sciences (SoMS)

John B. Kwok

University of New South Wales (UNSW) - School of Medical Sciences (SoMS)

Bryce K. England

National Institutes of Health

The International ALS Genomics Consortium

The ITALSGEN Consortium

The FALS Sequencing Consortium

The American Genome Center

Pentti Tienari

University of Massachusetts Worcester - Department of Neurology

David J. Stone

University of Massachusetts Worcester - Department of Neurology

Karen E. Morrison

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

Pamela J. Shaw

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

Ammar Al-Chalabi

University of London - Maurice Wohl Clinical Neuroscience Institute

Robert H. Brown Jr.

University of Massachusetts Worcester - Department of Neurology

Maura Brunetti

ASO OIRM-S.Anna

Andrea Calvo

University of Turin - Department of Neurosciences

Gabriele Mora

Azienda Ospedaliera Universitaria Maggiore della Carità - ALS Center

Marc Gotkine

Hebrew University of Jerusalem

Chris Shaw

University of London - Maurice Wohl Clinical Neuroscience Institute

John E. Landers

University of Massachusetts Worcester - Department of Neurology

Adriano Chiò

University of Massachusetts Worcester - Department of Neurology

Thomas O. Crawford

Johns Hopkins University

Bradley Smith

University of London - Maurice Wohl Clinical Neuroscience Institute

Bryan J. Traynor

University of Massachusetts Worcester - Department of Neurology

More...

Abstract

SPTLC1 encodes a critical subunit of serine palmitoyltransferase, the enzyme catalyzing the first and rate-limiting step in de novo sphingolipid biosynthesis, and mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A. Using exome sequencing, we identified a de novo coding variant in SPTLC1 in an individual diagnosed with juvenile-onset amyotrophic lateral sclerosis (ALS), and confirmed its pathogenicity by showing elevated plasma levels of neurotoxic deoxymethyl-sphinganine. We also found SPTLC1 mutations in 0.34% of 5,607 ALS cases, and immunohistochemically confirmed the expression of SPTLC1 in spinal cord motor neurons, supporting their role in the pathogenesis of this fatal neurodegenerative disease. Toxicity of deoxymethyl-sphinganine was demonstrated in HEK293FT cells, and could be corrected by L-serine supplementation. Our data broaden the phenotype associated with SPTLC1. Furthermore, nutritional supplementation with serine may be beneficial if instituted at an early stage among patients carrying mutations in SPTLC1.

Keywords: amyotrophic lateral sclerosis, genomics, de novo mutation, sphingolipid metabolism, SPTLC1, serine nutritional supplementation, deoxymethyl-sphinganine, individualized medicine

Suggested Citation

Janel, Johnson O. and Chia, Ruth and Kumaran, Ravindran and Alahmady, Nada and Abramzon, Yevgeniya and Faghri, Faraz and Renton, Alan and Topp, Simon D. and Pliner, Hannah A. and Gibbs, J. Raphael and Ding, Jinhui and Smith, Nathan and Landeck, Natalie and Nalls, Michael A. and Cookson, Mark R. and Pletnikova, Olga and Troncoso, Juan and Scholz, Sonja W. and Sabir, Marya S. and Ahmed, Sarah and Dalgard, Clifton L. and Troakes, Claire and Jones, Ashley R. and Shatunov, Aleksey and Iacoangeli, Alfredo and Al Khleifat, Ahmad and Ticozzi, Nicola and Silani, Vincenzo and Gellera, Cinzia and Blair, Ian P. and Dobson-Stone, Carol and Kwok, John B. and England, Bryce K. and Consortium, The International ALS Genomics and Consortium, The ITALSGEN and Consortium, The FALS Sequencing and Center, The American Genome and Tienari, Pentti and Stone, David J. and Morrison, Karen E. and Shaw, Pamela J. and Al-Chalabi, Ammar and Brown Jr., Robert H. and Brunetti, Maura and Calvo, Andrea and Mora, Gabriele and Gotkine, Marc and Shaw, Chris and Landers, John E. and Chiò, Adriano and Crawford, Thomas O. and Smith, Bradley and Traynor, Bryan J., Mutations in the Sphingolipid Pathway Gene SPTLC1 are a Cause of Amyotrophic Lateral Sclerosis (June 5, 2019). NEURON-D-19-00735. Available at SSRN: https://ssrn.com/abstract=3399502 or http://dx.doi.org/10.2139/ssrn.3399502
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Johnson O. Janel

National Institutes of Health - Neuromuscular Diseases Research Section ( email )

Bethesda, MD 20892
United States

Ruth Chia (Contact Author)

National Institutes of Health - Neuromuscular Diseases Research Section

Bethesda, MD 20892
United States

Ravindran Kumaran

National Institutes of Health (NIH) ( email )

9000 Rockville Pike
Bethesda, MD 20892
United States

Nada Alahmady

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

Strand
London, England WC2R 2LS
United Kingdom

Yevgeniya Abramzon

National Institutes of Health - Neuromuscular Diseases Research Section

Bethesda, MD 20892
United States

Faraz Faghri

National Institutes of Health - Molecular Genetics Section

Bethseda, MD 20892
United States

Alan Renton

National Institutes of Health - Neuromuscular Diseases Research Section ( email )

Bethesda, MD 20892
United States

Simon D. Topp

United Kingdom Dementia Research Institute Centre

Gower Street
London, WC1E 6BT
United Kingdom

Hannah A. Pliner

National Institutes of Health - Neurodegenerative Diseases Research Unit

Bethesda, MD 20892
United States

J. Raphael Gibbs

National Institutes of Health - Computational Biology Core

Building 31, Room 5C27
31 Center Drive, MSC 2292
Bethesda, MD 20892
United States

Jinhui Ding

National Institutes of Health - Computational Biology Core

Building 31, Room 5C27
31 Center Drive, MSC 2292
Bethesda, MD 20892
United States

Nathan Smith

National Institutes of Health

Washington, DC 20551
United States

Natalie Landeck

National Institutes of Health (NIH) ( email )

9000 Rockville Pike
Bethesda, MD 20892
United States

Michael A. Nalls

National Institutes of Health - Laboratory of Neurogenetics ( email )

Bethesda, MD 20892
United States

Mark R. Cookson

National Institutes of Health (NIH) ( email )

9000 Rockville Pike
Bethesda, MD 20892
United States

Olga Pletnikova

Johns Hopkins University - School of Medicine

733 North Broadway
Suite G-49
Baltimore, MD 21205-2196
United States

Juan Troncoso

Johns Hopkins University - Department of Pathology

Baltimore, MD 21231
United States

Sonja W. Scholz

National Institutes of Health - Neurodegenerative Diseases Research Unit

Bethesda, MD
United States

Marya S. Sabir

National Institutes of Health - Neurodegenerative Diseases Research Unit

Bethesda, MD
United States

Sarah Ahmed

National Institutes of Health - Neurodegenerative Diseases Research Unit

9000 Rockville Pike
Bethesda, MD 20892
United States

Clifton L. Dalgard

Uniformed Services University of the Health Sciences

4301 Jones Bridge Road
Bethesda, MD 20814
United States

Claire Troakes

United Kingdom Dementia Research Institute Centre

Gower Street
London, WC1E 6BT
United Kingdom

Ashley R. Jones

University of London - Maurice Wohl Clinical Neuroscience Institute

Strand
London, England WC2R 2LS
United Kingdom

Aleksey Shatunov

University of London - Maurice Wohl Clinical Neuroscience Institute

Strand
London, England WC2R 2LS
United Kingdom

Alfredo Iacoangeli

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

Strand
London, England WC2R 2LS
United Kingdom

Ahmad Al Khleifat

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

Strand
London, England WC2R 2LS
United Kingdom

Nicola Ticozzi

University of Milan - Department of Neurology and Laboratory of Neuroscience

Milan
Italy

Vincenzo Silani

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

Cinzia Gellera

Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ - Unit of Genetics of Neurodegenerative and Metabolic Diseases

Milan, 20133
Italy

Ian P. Blair

Macquarie University - Centre for MND Research

NSW 2109
Australia

Carol Dobson-Stone

University of New South Wales (UNSW) - School of Medical Sciences (SoMS) ( email )

Wallace Wurth Building
Sydney, NSW 2052
Australia

John B. Kwok

University of New South Wales (UNSW) - School of Medical Sciences (SoMS)

Wallace Wurth Building
Sydney, NSW 2052
Australia

Bryce K. England

National Institutes of Health ( email )

9000 Rockville Pike
Bethesda, MD 20892
United States

Pentti Tienari

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

David J. Stone

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

Karen E. Morrison

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

Southampton
United Kingdom

Pamela J. Shaw

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

385a Glossop Road
Sheffield
United Kingdom

Ammar Al-Chalabi

University of London - Maurice Wohl Clinical Neuroscience Institute

Strand
London, England WC2R 2LS
United Kingdom

Robert H. Brown Jr.

University of Massachusetts Worcester - Department of Neurology ( email )

Worcester, MA
United States

Maura Brunetti

ASO OIRM-S.Anna ( email )

Italy

Andrea Calvo

University of Turin - Department of Neurosciences

Via Verdi, 8
Torino, 10124
Italy

Gabriele Mora

Azienda Ospedaliera Universitaria Maggiore della Carità - ALS Center

Novara
Italy

Marc Gotkine

Hebrew University of Jerusalem ( email )

Mount Scopus
Jerusalem, IL Jerusalem 91905
Israel

Chris Shaw

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

Strand
London, England WC2R 2LS
United Kingdom

John E. Landers

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

Adriano Chiò

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

Thomas O. Crawford

Johns Hopkins University

Baltimore, MD 20036-1984
United States

Bradley Smith

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

Strand
London, England WC2R 2LS
United Kingdom

Bryan J. Traynor

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

No contact information is available for The International ALS Genomics Consortium
No contact information is available for The ITALSGEN Consortium
No contact information is available for The FALS Sequencing Consortium
No contact information is available for The American Genome Center

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