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.
Supported by the Deutsche Forschungsgemeinschaft (G.N.)
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Novarino G, Fenstermaker A, Zaki M, et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014;343(6170):506-511. doi:10.1126/science.1247363
Novarino, G., Fenstermaker, A., Zaki, M., Hofree, M., Silhavy, J., Heiberg, A., … Gleeson, J. (2014). Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science, 343(6170), 506–511. https://doi.org/10.1126/science.1247363
Novarino, Gaia, Ali Fenstermaker, Maha Zaki, Matan Hofree, Jennifer Silhavy, Andrew Heiberg, Mostafa Abdellateef, et al. “Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders.” Science 343, no. 6170 (2014): 506–11. https://doi.org/10.1126/science.1247363.
G. Novarino et al., “Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders,” Science, vol. 343, no. 6170, pp. 506–511, 2014.
Novarino G, Fenstermaker A, Zaki M, Hofree M, Silhavy J, Heiberg A, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al Aama J, Abdel Salam G, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben Omran T, Mojahedi F, Mahmoud I, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al Allawi N, Bindu P, Azam M, Günel M, Caglayan A, Bilgüvar K, Tolun A, Issa M, Schroth J, Spencer E, Rosti R, Akizu N, Vaux K, Johansen A, Koh A, Megahed H, Dürr A, Brice A, Stévanin G, Gabriel S, Ideker T, Gleeson J. 2014. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 343(6170), 506–511.
Novarino, Gaia, et al. “Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders.” Science, vol. 343, no. 6170, American Association for the Advancement of Science, 2014, pp. 506–11, doi:10.1126/science.1247363.