Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders

被引：431

作者：

Novarino, Gaia ^{[1
]}

Fenstermaker, Ali G. ^{[1
]}

Zaki, Maha S. ^{[4
]}

Hofree, Matan ^{[2
,3
]}

Silhavy, Jennifer L. ^{[1
]}

Heiberg, Andrew D. ^{[1
]}

Abdellateef, Mostafa ^{[1
]}

Rosti, Basak ^{[1
]}

Scott, Eric ^{[1
]}

Mansour, Lobna ^{[5
]}

Masri, Amira ^{[6
]}

Kayserili, Hulya ^{[7
]}

Al-Aama, Jumana Y. ^{[8
]}

Abdel-Salam, Ghada M. H. ^{[4
]}

Karminejad, Ariana ^{[9
]}

Kara, Majdi ^{[10
]}

Kara, Bulent ^{[11
]}

Bozorgmehri, Bita ^{[9
]}

Ben-Omran, Tawfeg ^{[12
]}

Mojahedi, Faezeh ^{[13
]}

Mahmoud, Iman Gamal El Din ^{[5
]}

Bouslam, Naima ^{[14
,15
]}

Bouhouche, Ahmed ^{[14
,15
]}

Benomar, Ali ^{[14
,15
]}

Hanein, Sylvain ^{[16
]}

Raymond, Laure ^{[16
]}

Forlani, Sylvie ^{[16
]}

Mascaro, Massimo ^{[1
]}

Selim, Laila ^{[5
]}

Shehata, Nabil ^{[17
]}

Al-Allawi, Nasir ^{[18
]}

Bindu, P. S. ^{[19
]}

Azam, Matloob ^{[20
]}

Gunel, Murat ^{[21
]}

Caglayan, Ahmet ^{[21
]}

Bilguvar, Kaya ^{[21
]}

Tolun, Aslihan ^{[22
]}

Issa, Mahmoud Y. ^{[4
]}

Schroth, Jana ^{[1
]}

Spencer, Emily G. ^{[1
]}

Rosti, Rasim O. ^{[1
]}

Akizu, Naiara ^{[1
]}

Vaux, Keith K. ^{[1
]}

Johansen, Anide ^{[1
]}

Koh, Alice A. ^{[1
]}

Megahed, Hisham ^{[4
]}

Durr, Alexandra ^{[16
,23
]}

Brice, Alexis ^{[16
,23
,24
]}

Stevanin, Giovanni ^{[16
,23
,24
,25
]}

Gabriel, Stacy B. ^{[26
]}

机构：

[1] Univ Calif San Diego, Howard Hughes Med Inst, San Diego, CA 92093 USA

[2] Univ Calif San Diego, Dept Comp Sci & Engn, San Diego, CA 92093 USA

[3] Univ Calif San Diego, Dept Med, San Diego, CA 92093 USA

[4] Natl Res Ctr, Human Genet & Genome Res Div, Clin Genet Dept, Cairo 12311, Egypt

[5] Cairo Univ, Childrens Hosp, Neurometabol Unit, Dept Pediat Neurol, Cairo 406, Egypt

[6] Univ Jordan, Dept Pediat, Div Child Neurol, Amman 11942, Jordan

[7] Istanbul Univ, Istanbul Fac Med, Dept Med Genet, TR-34093 Istanbul, Turkey

[8] King Abdulaziz Univ, Dept Med Genet, Jeddah 21413, Saudi Arabia

[9] Kariminejad Najmabadi Pathol & Genet Ctr, Tehran, Iran

[10] Tripoli Childrens Hosp, Dept Pediat, Tripoli, Libya

[11] Kocaeli Univ, Fac Med, Dept Pediat Neurol, TR-41380 Umuttepe, Kocaeli, Turkey

[12] Hamad Med Corp, Dept Pediat, Clin & Metab Genet Div, Doha 3050, Qatar

[13] Mashhad Med Genet Counseling Ctr, Mashhad 91767, Iran

[14] Univ Mohammed V Souissi, ERMN, Rabat 6402, Morocco

[15] Univ Mohammed V Souissi, CRECET, Rabat 6402, Morocco

[16] Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, INSERM U1127,CNRS UMR7225,UMR S975, F-75013 Paris, France

[17] Saudi German Hosp, Dept Pediat & Neonatol, Riyadh, Saudi Arabia

[18] Univ Dohuk, Sch Med, Dept Pathol, Dohuk, Iraq

[19] Natl Inst Mental Hlth & Neurosci, Dept Neurol, Bangalore 560029, Karnataka, India

[20] Wah Med Coll, Dept Pediat & Child Neurol, Wah Cantt, Pakistan

[21] Yale Univ, Sch Med, Dept Genet & Neurosurg, New Haven, CT 06510 USA

[22] Bogazici Univ, Dept Mol Biol & Genet, TR-34342 Istanbul, Turkey

[23] Hop La Pitie Salpetriere, AP HP, F-75013 Paris, France

[24] Inst Cerveau & Moelle Epiniere, F-75013 Paris, France

[25] Ecole Prat Hautes Etud, Inst Cerveau & Moelle Epiniere, Lab Neurogenet, F-75013 Paris, France

[26] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA

来源：

SCIENCE | 2014年 / 343卷 / 6170期

关键词：

HEREDITARY SPASTIC PARAPLEGIA; ENDOPLASMIC-RETICULUM; GOLGI-APPARATUS; PROTEIN; MUTATIONS; ARCHITECTURE; CYTOKINESIS; TRANSPORT; PATHWAYS; SUBUNIT;

D O I：

10.1126/science.1247363

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

引用

页码：506 / 511

页数：6

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