Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein

被引：100

作者：

Farhan, Sali M. K. ^{[1
,2
,3
,4
]}

Howrigan, Daniel P. ^{[1
,2
,3
,4
]}

Abbott, Liam E. ^{[1
,2
,3
]}

Klim, Joseph R. ^{[5
]}

Topp, Simon D. ^{[6
]}

Byrnes, Andrea E. ^{[1
,2
,3
,4
]}

Churchhouse, Claire ^{[1
,2
,3
,4
]}

Phatnani, Hemali ^{[7
]}

Smith, Bradley N. ^{[6
]}

Rampersaud, Evadnie ^{[8
]}

Wu, Gang ^{[8
]}

Wuu, Joanne ^{[9
]}

Shatunov, Aleksey ^{[10
]}

Iacoangeli, Alfredo ^{[10
,11
]}

Al Khleifat, Ahmad ^{[10
]}

Mordes, Daniel A. ^{[5
]}

Ghosh, Sulagna ^{[4
,5
]}

Eggan, Kevin ^{[4
,5
]}

Rademakers, Rosa ^{[12
]}

McCauley, Jacob L. ^{[13
,14
]}

Schuele, Rebecca ^{[15
,16
]}

Zuchner, Stephan ^{[13
,14
]}

Benatar, Michael ^{[9
]}

Taylor, J. Paul ^{[17
,18
]}

Nalls, Michael ^{[19
,20
]}

Gotkine, Marc ^{[21
]}

Shaw, Pamela J. ^{[22
]}

Morrison, Karen E. ^{[23
,24
]}

Al-Chalabi, Ammar ^{[9
,25
]}

Traynor, Bryan ^{[20
,26
]}

Shaw, Christopher E. ^{[6
,27
]}

Goldstein, David B. ^{[28
]}

Harms, Matthew B. ^{[29
]}

Daly, Mark J. ^{[1
,2
,3
,4
]}

Neale, Benjamin M. ^{[1
,2
,3
,4
]}

机构：

[1] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[2] Harvard Med Sch, Boston, MA 02115 USA

[3] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA

[4] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[5] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[6] Kings Coll London, Inst Psychiat Psychol & Neurosci, Maurice Wohl Clin Neurosci Inst, United Kingdom Dementia Res Inst Ctr, London, England

[7] New York Genome Ctr, Ctr Genom Neurodegenerat Dis, New York, NY USA

[8] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA

[9] Univ Miami, Dept Neurol, Miami, FL USA

[10] Kings Coll London, Maurice Wohl Clin Neurosci Inst, Dept Basic & Clin Neurosci, London, England

[11] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Biostat & Hlth Informat, London, England

[12] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[13] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA

[14] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn, Dept Human Genet, Miami, FL 33136 USA

[15] Univ Tubingen, German Ctr Neurodegenerat Dis, Ctr Neurol, Tubingen, Germany

[16] Univ Tubingen, German Ctr Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany

[17] Howard Hughes Med Inst, Chevy Chase, MD USA

[18] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, 332 N Lauderdale St, Memphis, TN 38105 USA

[19] NIA, Mol Genet Sect, Neurogenet Lab, Bethesda, MD 20892 USA

[20] Data Tecn Int, Glen Echo, MD USA

[21] Hadassah Hebrew Univ, Med Ctr, Agnes Ginges Ctr Human Neurogenet, Dept Neurol, Jerusalem, Israel

[22] Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, Sheffield, S Yorkshire, England

[23] Univ Southampton, Fac Med, Southampton, Hants, England

[24] Univ Hosp Southampton, Dept Neurol, Southampton, Hants, England

[25] Kings Coll Hosp London, Dept Neurol, London, England

[26] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA

[27] Univ Auckland, Ctr Brain Res, Auckland, New Zealand

[28] Columbia Univ, Inst Genom Med, New York, NY USA

[29] Columbia Univ, Dept Neurol, New York, NY USA

来源：

NATURE NEUROSCIENCE | 2019年 / 22卷 / 12期

基金：

英国惠康基金; 英国医学研究理事会; 英国经济与社会研究理事会;

关键词：

LOSS-OF-FUNCTION; PARKINSONS-DISEASE; ANALYSES IDENTIFY; ALPHA-SYNUCLEIN; VARIANTS; DEMENTIA; MODEL; PRION; AGGREGATION; EXPRESSION;

D O I：

10.1038/s41593-019-0530-0

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

To discover novel genes underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry-matched controls. We observed a significant excess of rare protein-truncating variants among ALS cases, and these variants were concentrated in constrained genes. Through gene level analyses, we replicated known ALS genes including SOD1, NEK1 and FUS. We also observed multiple distinct protein-truncating variants in a highly constrained gene, DNAJC7. The signal in DNAJC7 exceeded genome-wide significance, and immunoblotting assays showed depletion of DNAJC7 protein in fibroblasts in a patient with ALS carrying the p.Arg156Ter variant. DNAJC7 encodes a member of the heat-shock protein family, HSP40, which, along with HSP70 proteins, facilitates protein homeostasis, including folding of newly synthesized polypeptides and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of aberrant proteins can occur and lead to protein aggregation, which is a pathological hallmark of neurodegeneration. Our results highlight DNAJC7 as a novel gene for ALS.

引用

页码：1966 / +

页数：12

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