Journal
SCIENCE
Volume 343, Issue 6170, Pages 506-511Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1247363
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Funding
- Deutsche Forschungsgemeinschaft
- Brain and Behavior Research Foundation
- NIH [R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101]
- French National Agency for Research
- Verum Foundation
- European Union
- Fondation Roger de Spoelberch
- Investissements d'avenir [ANR-10-IAIHU-06]
- Princess Al Jawhara Center of Excellence in Research of Hereditary Disorders
- Inherited Disease Research [HHSN268200782096C, HHSN268201100011I, N01-CO-12400]
- [P41GM103504]
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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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