Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

被引：963

作者：

Johnson, Jane O. ^{[1
]}

Mandrioli, Jessica ^{[3
,4
]}

Benatar, Michael ^{[5
]}

Abramzon, Yevgeniya ^{[1
]}

Van Deerlin, Vivianna M. ^{[6
]}

Trojanowski, John Q. ^{[6
]}

Gibbs, J. Raphael ^{[8
,9
]}

Brunetti, Maura ^{[10
]}

Gronka, Susan ^{[5
]}

Wuu, Joanne ^{[5
]}

Ding, Jinhui

McCluskey, Leo ^{[7
]}

Martinez-Lage, Maria ^{[6
]}

Falcone, Dana ^{[6
]}

Hernandez, Dena G. ^{[2
,8
,9
]}

Arepalli, Sampath ^{[2
]}

Chong, Sean ^{[2
]}

Schymick, Jennifer C. ^{[1
]}

Rothstein, Jeffrey ^{[11
]}

Landi, Francesco ^{[12
]}

Wang, Yong-Dong ^{[13
]}

Calvo, Andrea ^{[14
]}

Mora, Gabriele ^{[15
]}

Sabatelli, Mario ^{[16
,17
]}

Monsurro, Maria Rosaria ^{[18
]}

Battistini, Stefania ^{[19
]}

Salvi, Fabrizio ^{[20
]}

Spataro, Rossella ^{[21
]}

Sola, Patrizia ^{[3
,4
]}

Borghero, Giuseppe ^{[22
]}

Galassi, Giuliana ^{[3
,4
]}

Scholz, Sonja W. ^{[2
,23
]}

Taylor, J. Paul ^{[13
]}

Restagno, Gabriella ^{[10
]}

Chio, Adriano ^{[14
]}

Traynor, Bryan J. ^{[1
,11
]}

机构：

[1] NIA, Neuromuscular Dis Res Grp, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[2] NIA, Mol Genet Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[3] S Agostino Estense Hosp, Dept Neurosci, I-41126 Modena, Italy

[4] Univ Modena, I-41126 Modena, Italy

[5] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[6] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[7] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA

[8] UCL, Dept Mol Neurosci, London WC1 3BG, England

[9] UCL, Reta Lila Weston Labs, Inst Neurol, London WC1 3BG, England

[10] ASO OIRMS Anna, Mol Genet Unit, Dept Clin Pathol, I-10126 Turin, Italy

[11] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA

[12] Univ Cattolica Sacro Cuore, Dept Gerontol Geriatr & Rehabil Med, I-00168 Rome, Italy

[13] St Jude Childrens Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA

[14] Univ Turin, Dept Neurosci, I-10126 Turin, Italy

[15] Salvatore Maugeri Fdn, ALS Ctr, I-20100 Milan, Italy

[16] Catholic Univ, Neurol Inst, I-10100 Rome, Italy

[17] ICOMM Assoc ALS Res, I-10100 Rome, Italy

[18] Univ Naples 2, Dept Neurol Sci, I-80138 Naples, Italy

[19] Univ Siena, Dept Neurosci, Neurol Sect, I-53100 Siena, Italy

[20] Bellaria Hosp, Dept Neurol, Ctr Diag & Cure Rare Dis, I-40100 Bologna, Italy

[21] Univ Palermo, Dept Clin Neurosci, I-90129 Palermo, Italy

[22] Univ Cagliari, Azienda Hosp, Neurol Clin, I-09042 Monserrato, Italy

[23] Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA

来源：

NEURON | 2010年 / 68卷 / 05期

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; VALOSIN-CONTAINING PROTEIN; FRONTOTEMPORAL LOBAR DEGENERATION; INCLUSION-BODY MYOPATHY; PAGET-DISEASE; DEMENTIA; BONE; TDP-43; P97; VCP/P97;

D O I：

10.1016/j.neuron.2010.11.036

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 similar to 1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.

引用

页码：857 / 864

页数：8

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