Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

Janel O Johnson; Jessica Mandrioli; Michael Benatar; Yevgeniya Abramzon; Vivianna M Van Deerlin; John Q Trojanowski; J. Raphael Gibbs; Maura Brunetti; Susan Gronka; Joanne Wuu; Jinhui Ding; Leo McCluskey; Maria Martinez-Lage; Dana Falcone; Dena G Hernandez; Sampath Arepalli; Sean Chong; Jennifer C Schymick; Jeffrey Rothstein; Francesco Landi; Yong-Dong Wang; Andrea Calvo; Gabriele Mora; Mario Sabatelli; Maria Rosaria Monsurrò; Stefania Battistini; Fabrizio Salvi; Rossella Spataro; Patrizia Sola; Giuseppe Borghero; Giuliana Galassi; Sonja W Scholz; J. Paul Taylor; Gabriella Restagno; Adriano Chiò; Bryan J Traynor; The ITALSGEN Consortium

doi:10.1016/j.neuron.2010.11.036

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Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

Journal article

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Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

Janel O Johnson, Jessica Mandrioli, Michael Benatar, Yevgeniya Abramzon, Vivianna M Van Deerlin, John Q Trojanowski, J. Raphael Gibbs, Maura Brunetti, Susan Gronka, Joanne Wuu, …

Neuron (Cambridge, Mass.), Vol.68(5), pp.857-864

2010

DOI: https://doi.org/10.1016/j.neuron.2010.11.036

PMCID: PMC3032425

PMID: 21145000

Abstract

Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein ( VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%–2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration. ► Exome sequencing was used to identify a mutation in VCP in a family with ALS ► Mutational screening indicates that VCP mutations account for ∼1%–2% of familial ALS ► Our data extend the clinical spectrum associated with IBMPFD syndrome to include ALS ► Identified defect in protein degradation pathway in motor neuron degeneration

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.765 Amyotrophic Lateral Sclerosis
Web Of Science research areas: Neurosciences
ESI research areas: Neuroscience & Behavior

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Title: Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
Creators: Janel O Johnson - Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA
Jessica Mandrioli - Department of Neuroscience, S. Agostino-Estense Hospital and University of Modena, 41126 Modena, Italy
Michael Benatar - Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
Yevgeniya Abramzon - Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA
Vivianna M Van Deerlin - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
John Q Trojanowski - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
J. Raphael Gibbs - Computational Biology Core, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA
Maura Brunetti - Molecular Genetics Unit, Department of Clinical Pathology, A.S.O. O.I.R.M.-S. Anna, 10126 Turin, Italy
Susan Gronka - Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
Joanne Wuu - Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
Jinhui Ding - Computational Biology Core, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA
Leo McCluskey - Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA
Maria Martinez-Lage - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Dana Falcone - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Dena G Hernandez - Molecular Genetics Unit, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA
Sampath Arepalli - Molecular Genetics Unit, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA
Sean Chong - Molecular Genetics Unit, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA
Jennifer C Schymick - Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA
Jeffrey Rothstein - Department of Neurology, Johns Hopkins Hospital, Baltimore, MD 21287, USA
Francesco Landi - Department of Gerontology, Geriatrics, and Rehabilitative Medicine, Catholic University of Sacred Heart, Rome, Italy
Yong-Dong Wang - Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Andrea Calvo - Department of Neuroscience, University of Turin, 10126 Turin, Italy
Gabriele Mora - ALS Center, Salvatore Maugeri Foundation, 20100 Milan, Italy
Mario Sabatelli - Neurological Institute, Catholic University and I.C.O.M.M. Association for ALS Research, 10100 Rome, Italy
Maria Rosaria Monsurrò - Department of Neurological Sciences, Second University of Naples, 80138 Naples, Italy
Stefania Battistini - Department of Neuroscience, Neurology Section, University of Siena, 53100 Siena, Italy
Fabrizio Salvi - Center for Diagnosis and Cure of Rare Diseases, Department of Neurology, Bellaria Hospital, 40100 Bologna, Italy
Rossella Spataro - Department of Clinical Neurosciences, University of Palermo, 90129 Palermo, Italy
Patrizia Sola - Department of Neuroscience, S. Agostino-Estense Hospital and University of Modena, 41126 Modena, Italy
Giuseppe Borghero - Neurological Clinic, Azienda Hospital, University of Cagliari, 09042 Monserrato-Cagliari, Italy
Giuliana Galassi - Department of Neuroscience, S. Agostino-Estense Hospital and University of Modena, 41126 Modena, Italy
Sonja W Scholz - Molecular Genetics Unit, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA
J. Paul Taylor - Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Gabriella Restagno - Molecular Genetics Unit, Department of Clinical Pathology, A.S.O. O.I.R.M.-S. Anna, 10126 Turin, Italy
Adriano Chiò - Department of Neuroscience, University of Turin, 10126 Turin, Italy
Bryan J Traynor - Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA
The ITALSGEN Consortium
Publication Details: Neuron (Cambridge, Mass.), Vol.68(5), pp.857-864
Publisher: Elsevier Inc
Academic Unit: Miller School of Medicine; UMMG Department of Neurology; UMMG Dept of Neurology - Neuromuscular Disorders Div
Language: English
Resource Type: Journal article
PMID: 21145000
PMCID: PMC3032425
Record Identifier: 991031600454302976