Amyotrophic lateral sclerosis (ALS) is an adult-onset, rapidly progressive and ultimately fatal neurodegenerative disease caused by the selective loss of motor neurons. Although most ALS cases are sporadic (SALS), ~10% are familial (FALS). To date, the underlying cause has been identified in only ~35% of all FALS cases: 20% are caused by mutations in SOD1, 5% in TARDBP and 5% in FUS. Variants in several other genes have been found in additional families to a lesser degree. Genetic studies have provided invaluable information for understanding of the pathogenesis of both FALS and SALS. Undoubtedly, the discovery of novel FALS- associated genes will dramatically further our knowledge of the cellular pathways that lead to motor neuron degeneration. Until now, it was not economically feasible to screen for rare variants at a genome-wide scale within disease-affected samples. However, the recent advances in automated, short-read DNA sequencing offer new solutions to this problem: it is now possible to sequence only protein-coding regions of the genome (exomes) to reduce costs while enriching for the discovery of highly penetrant variants. The purpose of this proposal is to identify novel causative genes for FALS using the approach of exome capture followed by short- read sequencing.
The Specific Aims of this proposal are to: (1) Perform exon capture and short-read sequencing of selected samples to identify candidate FALS-specific variants. Exome capture and short-read sequencing will be performed for 2 distantly-related affected members of 10 ALS afflicted families (20 FALS). A primary list of candidate variants causative for ALS will then be created using a series of bioinformatic filtering steps. (2) Identify the variants derived from exome sequencing that are specific for FALS. Candidate variants will be interrogated by genotyping a panel of ~1,100 control samples as well as an additional panel of ~200 FALS. Variants detected in FALS, but not within the control population, are highly suggestive of a causative change. (3) Determine if candidate FALS genes show different mutations in additional FALS families. Candidate genes harboring FALS-specific variants will be sequenced in ~200 FALS samples to identify additional variants. Genes with multiple alterations in FALS not observed in control populations will be considered causal. Our proposed studies will identify novel candidate genes whose mutations cause FALS. In the long term, understanding the genetic causes of ALS will facilitate our understanding of all forms of ALS as well as assisting in the development of diagnostics and therapies to extend the lifespan of ALS patients.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an adult-onset, rapidly progressive and ultimately fatal neurodegenerative disease caused by the selective loss of motor neurons. The underlying genetic cause of familial forms of ALS has been identified in only ~35% of cases. The purpose of this proposal is to identify novel causative genes for familial ALS which will facilitate our understanding how such defects lead to disease as well as assisting in the development of diagnostics and therapies to extend the lifespan of patients.
|Nicolas, Aude (see original citation for additional authors) (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron 97:1268-1283.e6|
|Project MinE ALS Sequencing Consortium (2018) Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis. Eur J Hum Genet 26:1537-1546|
|van der Spek, Rick A; van Rheenen, Wouter; Pulit, Sara L et al. (2018) Reconsidering the causality of TIA1 mutations in ALS. Amyotroph Lateral Scler Frontotemporal Degener 19:1-3|
|White, Matthew A; Kim, Eosu; Duffy, Amanda et al. (2018) TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD. Nat Neurosci 21:552-563|
|Perez Carrion, Maria; Pischedda, Francesca; Biosa, Alice et al. (2018) The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1. Front Mol Neurosci 11:64|
|Smith, Bradley N; Topp, Simon D; Fallini, Claudia et al. (2017) Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. Sci Transl Med 9:|
|McLaughlin, Russell L; Schijven, Dick; van Rheenen, Wouter et al. (2017) Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nat Commun 8:14774|
|Wu, Chi-Hong; Giampetruzzi, Anthony; Tran, Helene et al. (2017) A Drosophila model of ALS reveals a partial loss of function of causative human PFN1 mutants. Hum Mol Genet 26:2146-2155|
|Fil, Daniel; DeLoach, Abigail; Yadav, Shilpi et al. (2017) Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease. Hum Mol Genet 26:686-701|
|Cooper-Knock, Johnathan; Robins, Henry; Niedermoser, Isabell et al. (2017) Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype. Front Mol Neurosci 10:370|
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