. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron. 2014 Oct 22;84(2):324-31. PubMed.


Please login to recommend the paper.


  1. The last 10 years have seen several major breakthroughs in ALS genetics, many resulting from genetic linkage studies in large, multigenerational families with the disease. However, these families are very rare and few remain that haven’t yet been analyzed for linkage with known ALS genes. Here, Landers and colleagues take a novel approach to circumvent this problem, performing exome sequencing on 363 familial ALS (fALS) cases and 31 related controls, and then subjecting the sequencing data to a genome-wide association study to identify genes with an enrichment of rare, potentially damaging variants in fALS cases compared to controls. They spiked in samples from patients who they knew had SOD1 mutations as a control and pulled these out as the top hit from the screen.

    The next-highest-ranking gene they identified is TUBA4A, encoding the Tubulin, alpha 4A protein. The identified association in this gene was due to five patients in their fALS cohort, each with a different non-synonymous mutation in highly-conserved residues of the gene. Critically, they go on to confirm this association by analyzing an independent set of 272 FALS cases and many thousands of controls.

    This paper, especially now that there are several large-scale international efforts at sporadic ALS exome sequencing underway, provides an excellent example of how to analyze the data to discover important new genetic associations, and to validate the discoveries with functional data. Beyond that, it seems that the tubulin mutations Landers and colleagues have discovered are going to be important for ALS in general. In my opinion, this manuscript provides a novel approach to identifying ALS-linked genes and may have identified one new ALS-associated gene, TUBA4A. The race is now on to figure out how tubulin fits into ALS pathogenesis and the field must now assess the TUBA4A gene in additional ALS patient cohorts.

  2. Smith et al. performed exome sequencing in a cohort of 363 index cases from ALS families (FALS). They used the control exome data from the NHLBI’s Exome Variant Server (n=4,300 European Americans) to compare aggregated counts of minor alleles in gene windows between cases and controls. Results showed a significant excess of TUBA4A in patients. This difference between cases and controls was replicated by studying an additional cohort of 272 FALS and 5,510 controls. Subsequent functional analyses revealed the destabilization of microtubules by the TUBA4A mutations identified.

    This is an interesting study making good use of publicly available exome sequencing-derived data. Although the cohorts of patients studied were small, the spike in a number of cases with known mutations (particularly, SOD1) and the use of these cases as positive controls for the genetic methods give robustness to the results.

    As the authors recognize, the main drawback of the aggregation of variants for comparison between cases and controls is the difficulty of attributing pathogenicity to specific variants. If the current results get to be independently replicated, it is clear that the TUBA4A gene is involved in ALS, however, it is rather unclear what role each of the variants identified has in disease. The authors refer to a set of eight variants (p.G43V, p.T145P, p.R215C, p.R320C/H, p.A383T, p.W407X and p.K430N); two of these (p.G43V and p.A383T) were found in controls in the replication stage.

    Looking at the data recently released by the Exome Aggregation Consortium (ExAC), which includes data derived from exome sequencing of more than 63,000 samples, a few of the mutations reported as possibly involved in ALS can be found in one or two individuals (p.G43V, one allele; p.R320C, two allele; and p.A383T, one allele). In particular, it is difficult to reconcile the genetic and functional data for the variant p.A383T that the authors detected in a control sample (as they did for p.G43V), but functionally shows significant impacts on microtubule polymerization and microtubule network stabilization.

    As the authors discuss, it is interesting to note that mutations in other members of the tubulin family cause both neurodevelopmental and neurodegenerative disorders, with defects responsible for the former occurring in proteins that are highly expressed during brain development but then wane with age, and the latter being associated with genes increasingly expressed  with age. It is also interesting that two of the cases with TUBA4A mutations have frontal cognitive decline in addition to ALS, spotlighting the potential for gene screens in FTD cohorts to turn up TUBA4A as well.

Make a Comment

To make a comment you must login or register.

This paper appears in the following:


  1. Novel Exome Screen Points to Tubulin as ALS Gene