期刊
NEURON
卷 84, 期 2, 页码 324-331出版社
CELL PRESS
DOI: 10.1016/j.neuron.2014.09.027
关键词
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资金
- Medical Research Council [G0600974, MR/L501529/1, MR/L016397/1, MR/K01014X/1, G1100695] Funding Source: Medline
- NIA NIH HHS [P50 AG025688] Funding Source: Medline
- NINDS NIH HHS [R01 NS073873, R01 NS065847] Funding Source: Medline
- Wellcome Trust [089701] Funding Source: Medline
- Motor Neurone Disease Association [TURNER/JAN13/944-795] Funding Source: Medline
- Direct For Mathematical & Physical Scien
- Division Of Mathematical Sciences [1309960] Funding Source: National Science Foundation
- Medical Research Council [MR/K01014X/1, G0600974, G1100695, MR/L501529/1, MR/L016397/1] Funding Source: researchfish
- Motor Neurone Disease Association [Turner/Jan13/944-795] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10082] Funding Source: researchfish
- MRC [MR/L016397/1, G1100695, G0600974, MR/K01014X/1] Funding Source: UKRI
Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.
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