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Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS.

Journal article published in 2014 by Bn Smith ORCID, Lh van den Berg, Nicola Ticozzi ORCID, Claudia Fallini, As Gkazi, Simon Topp ORCID, Kp Kenna, El Scotter ORCID, Jw Miller, Jason Kost, Ew Danielson, Pamela Keagle, Ea Lewis, Daniela Calini, Anneloor Lma Ten Asbroek and other authors.
This paper is available in a repository.
This paper is available in a repository.

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UNLABELLED: 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. VIDEO ABSTRACT: