Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders Journal Article

Author(s): Novarino, Gaia; Fenstermaker, Ali G; Zaki, Maha S; Hofree, Matan; Silhavy, Jennifer L; Heiberg, Andrew D; Abdellateef, Mostafa; Rosti, Başak; Scott, Eric M; Mansour, Lobna A; Masri, Amira T; Kayserili, Hülya; Al-Aama, Jumana Y; Abdel-Salam, Ghada M; Karminejad, Ariana; Kara, Majdi; Kara, Bülent; Bozorgmehri, Bita; Ben-Omran, Tawfeg I; Mojahedi, Faezeh; Mahmoud, Iman G; Bouslam, Naïma; Bouhouche, Ahmed; Benomar, Ali; Hanein, Sylvain; Raymond, Laure; Forlani, Sylvie; Mascaro, Massimo; Selim, Laila A; Shehata, Nabil; Al-Allawi, Nasir A; Bindu, Parayil S; Azam, Matloob G; Günel, Murat; Caglayan, Ahmet O; Bilgüvar, Kaya; Tolun, Aslihan; Issa, Mahmoud Y; Schroth, Jana; Spencer, Emily G; Rosti, Rasim Ö; Akizu, Naiara; Vaux, Keith K; Johansen, Anide; Koh, Alice A; Megahed, Hisham; Dürr, Alexandra; Brice, Alexis; Stévanin, Giovanni G; Gabriel, Stacy B; Ideker, Trey G; Gleeson, Joseph G
Article Title: Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders
Affiliation IST Austria
Abstract: 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.
Keywords: Mutation; Genome; molecular analysis; Neurology; disease incidence; genetic analysis; nervous system disorder
Journal Title: Science
Volume: 343
Issue 6170
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2014-01-01
Start Page: 506
End Page: 511
Sponsor: Supported by the Deutsche Forschungsgemeinschaft (G.N.); the Brain and Behavior Research Foundation (A.G.F.); NIH R01NS041537, R01NS048453, R01NS052455, P01HD070494, and P30NS047101 (J.G.G.); French National Agency for Research (G.S., A.D.); the Verum Fou
DOI: 10.1126/science.1247363
Open access: no