Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders

Gaia Novarino; Ali G Fenstermaker; Maha S Zaki; Matan Hofree; Jennifer L Silhavy; Andrew D Heiberg; Mostafa Abdellateef; Basak Rosti; Eric Scott; Lobna Mansour; Amira Masri; Hulya Kayserili; Jumana Y Al-Aama; Ghada M H Abdel-Salam; Ariana Karminejad; Majdi Kara; Bulent Kara; Bita Bozorgmehri; Tawfeg Ben-Omran; Faezeh Mojahedi; Iman Gamal El Din Mahmoud; Naima Bouslam; Ahmed Bouhouche; Ali Benomar; Sylvain Hanein; Laure Raymond; Sylvie Forlani; Massimo Mascaro; Laila Selim; Nabil Shehata; Nasir Al-Allawi; P S Bindu; Matloob Azam; Murat Gunel; Ahmet Caglayan; Kaya Bilguvar; Aslihan Tolun; Mahmoud Y Issa; Jana Schroth; Emily G Spencer; Rasim O Rosti; Naiara Akizu; Keith K Vaux; Anide Johansen; Alice A Koh; Hisham Megahed; Alexandra Durr; Alexis Brice; Giovanni Stevanin; Stacy B Gabriel; Trey Ideker; Joseph G Gleeson

doi:10.1126/science.1247363

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Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders

Journal article

Peer reviewed

Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders

Gaia Novarino, Ali G Fenstermaker, Maha S Zaki, Matan Hofree, Jennifer L Silhavy, Andrew D Heiberg, Mostafa Abdellateef, Basak Rosti, Eric Scott, Lobna Mansour, …

Science (American Association for the Advancement of Science), Vol.343(6170), pp.506-511

31/01/2014

DOI: https://doi.org/10.1126/science.1247363

PMCID: PMC4157572

PMID: 24482476

Abstract

Animals

Axons - physiology

Biological Transport - genetics

Cohort Studies

Exome - genetics

Gene Regulatory Networks

Genetic Association Studies

Humans

Motor Neuron Disease - genetics

Mutation

Neurons - metabolism

Nucleotides - genetics

Nucleotides - metabolism

Pyramidal Tracts - metabolism

Sequence Analysis, DNA

Spastic Paraplegia, Hereditary - genetics

Synapses - physiology

Transcriptome

Zebrafish

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.

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Title: Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders
Creators - without role: Gaia Novarino - Howard Hughes Medical Institute
Ali G Fenstermaker - Howard Hughes Medical Institute
Maha S Zaki - National Water Research Center
Matan Hofree - University of California, San Diego
Jennifer L Silhavy - Howard Hughes Medical Institute
Andrew D Heiberg - Howard Hughes Medical Institute
Mostafa Abdellateef - Howard Hughes Medical Institute
Basak Rosti - Howard Hughes Medical Institute
Eric Scott - Howard Hughes Medical Institute
Lobna Mansour - Cairo University
Amira Masri - University of Jordan
Hulya Kayserili - Istanbul University
Jumana Y Al-Aama - King Abdulaziz University
Ghada M H Abdel-Salam - National Water Research Center
Ariana Karminejad - Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran
Majdi Kara - Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya
Bulent Kara - Kocaeli Üniversitesi
Bita Bozorgmehri - Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran
Tawfeg Ben-Omran - Hamad Medical Corporation
Faezeh Mojahedi - Center for Human Genetics
Iman Gamal El Din Mahmoud - Cairo University
Naima Bouslam - Direction de l’Epidémiologie et de Lutte contre les Maladies
Ahmed Bouhouche - Direction de l’Epidémiologie et de Lutte contre les Maladies
Ali Benomar - Direction de l’Epidémiologie et de Lutte contre les Maladies
Sylvain Hanein - Institut du Cerveau
Laure Raymond - Institut du Cerveau
Sylvie Forlani - Institut du Cerveau
Massimo Mascaro - Howard Hughes Medical Institute
Laila Selim - Cairo University
Nabil Shehata - Riyadh Armed Forces Hospital
Nasir Al-Allawi - University of Duhok
P S Bindu - National Institute of Mental Health and Neurosciences
Matloob Azam - University of Wah
Murat Gunel - Yale University
Ahmet Caglayan - Yale University
Kaya Bilguvar - Yale University
Aslihan Tolun - Boğaziçi University
Mahmoud Y Issa - National Water Research Center
Jana Schroth - Howard Hughes Medical Institute
Emily G Spencer - Howard Hughes Medical Institute
Rasim O Rosti - Howard Hughes Medical Institute
Naiara Akizu - Howard Hughes Medical Institute
Keith K Vaux - Howard Hughes Medical Institute
Anide Johansen - Howard Hughes Medical Institute
Alice A Koh - Howard Hughes Medical Institute
Hisham Megahed - National Water Research Center
Alexandra Durr - Institut du Cerveau
Alexis Brice - Inserm
Giovanni Stevanin - Inserm
Stacy B Gabriel - Broad Institute
Trey Ideker - University of California, San Diego
Joseph G Gleeson - University of California, San Diego
Publication Details: Science (American Association for the Advancement of Science), Vol.343(6170), pp.506-511
Grant note: P01HD070494 / NICHD NIH HHS Howard Hughes Medical Institute P41 GM103504 / NIGMS NIH HHS U54HG003067 / NHGRI NIH HHS HHSN268201100011 / PHS HHS U54HG006504 / NHGRI NIH HHS N01-CO-12400 / NCI NIH HHS P30NS047101 / NINDS NIH HHS P30 NS047101 / NINDS NIH HHS U54 HG006504 / NHGRI NIH HHS R01NS041537 / NINDS NIH HHS HHSN268200782096C / NHGRI NIH HHS U54 HG003067 / NHGRI NIH HHS R01 NS052455 / NINDS NIH HHS R01NS048453 / NINDS NIH HHS R01 NS041537 / NINDS NIH HHS R01NS052455 / NINDS NIH HHS N01CO12400 / NCI NIH HHS HHSN268200782096C / NHLBI NIH HHS P01 HD070494 / NICHD NIH HHS HHSN268201100011C / NHLBI NIH HHS R01 NS048453 / NINDS NIH HHS HHSN268201100011I / NHLBI NIH HHS
Identifiers: 9939093308331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article