Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders

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...

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Published in:Science (American Association for the Advancement of Science) 2014-01, Vol.343 (6170), p.506-511
Main Authors: Novarino, Gaia, Fenstermaker, Ali G., Zaki, Maha S., Hofree, Matan, Silhavy, Jennifer L., Heiberg, Andrew D., Abdellateef, Mostafa, Rosti, Basak, Scott, Eric, Mansour, Lobna, Masri, Amira, Kayserili, Hulya, Al-Aama, Jumana Y., Abdel-Salam, Ghada M. H., Karminejad, Ariana, Kara, Majdi, Kara, Bulent, Bozorgmehri, Bita, Ben-Omran, Tawfeg, Mojahedi, Faezeh, Mahmoud, Iman Gamal El Din, Bouslam, Naima, Bouhouche, Ahmed, Benomar, Ali, Hanein, Sylvain, Raymond, Laure, Forlani, Sylvie, Mascaro, Massimo, Selim, Laila, Shehata, Nabil, Al-Allawi, Nasir, Bindu, P.S., Azam, Matloob, Gunel, Murat, Caglayan, Ahmet, Bilguvar, Kaya, Tolun, Aslihan, Issa, Mahmoud Y., Schroth, Jana, Spencer, Emily G., Rosti, Rasim O., Akizu, Naiara, Vaux, Keith K., Johansen, Anide, Koh, Alice A., Megahed, Hisham, Durr, Alexandra, Brice, Alexis, Stevanin, Giovanni, Gabriel, Stacy B., Ideker, Trey, Gleeson, Joseph G.
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Animals
Axons - physiology
Biological Transport - genetics
Cohort Studies
Exome - genetics
Gene Regulatory Networks
Genes
Genetic Association Studies
Genetic loci
Genetic mutation
Genetics
Heat shock proteins
Humans
Medical genetics
Motor Neuron Disease - genetics
Mutation
Network Analysis
Neurodegeneration
Neurodegenerative diseases
Neurological disorders
Neurons
Neurons - metabolism
Nucleotides
Nucleotides - genetics
Nucleotides - metabolism
Proteins
Pyramidal Tracts - metabolism
RESEARCH ARTICLE
Schoenlein Henoch purpura
Sequence Analysis, DNA
Spastic Paraplegia, Hereditary - genetics
Synapses - physiology
Transcriptome
Zebrafish
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Summary: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.
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.1247363