. Structural basis for mutation-induced destabilization of profilin 1 in ALS. Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):7984-9. Epub 2015 Jun 8 PubMed.


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  1. Boopathy et al. provide functional evidence that profilin 1 (PFN1) mutations are pathogenic because they create a cavity in the protein that severely destabilizes it and makes it prone to aggregation, in turn providing mechanistic evidence for the proposed loss-of-function mechanism.

    This study is a nice example of how the identification of a rare gene, in this case for ALS, can lead to important mechanistic insights into disease biology, and offer leads for therapy development.

    Although initial genetic reports seemed to suggest that PFN1 p.E177G is a benign polymorphism rather than a causal mutation, since it is found in the healthy control population, continued genetic screening in different European populations and meta-analysis showed robust genetic evidence that p.E117G operates as a low-penetrant susceptibility factor that is able to triple ALS risk (Smith et al., 2015). 

    In line with this, Boopathy et al. demonstrate that E117G shows a similar trend on protein structure and stability to the pathogenic mutations, but with a more subtle effect, somewhere between the wild-type and causal mutations, yet closer to the wild-type. These observations fit exactly with what you would expect from a risk factor, and likely E177G leads to disease in conjunction with other genetic and/or epigenetic factors that together lower the threshold for developing ALS.

    There is now good statistical evidence that PFN1 p.E177G is genetically associated with ALS and able to significantly increase risk to develop disease. Overall frequencies show an average prevalence of 0.3 percent in patients versus just 0.1 percent in controls. Moreover,  the observation by Smith et al. of E177G in one index patient with disease onset of 62 years, an unaffected mother who died at age 62, and a maternal first cousin who died of ALS at age 40, is suggestive for co-segregation of the mutation with reduced penetrance. Also the E117 residue is fully conserved in mammals.

    Taken together, I would classify E177G as a low-frequency variant able to cause disease, but with reduced penetrance.


    . Novel mutations support a role for Profilin 1 in the pathogenesis of ALS. Neurobiol Aging. 2015 Mar;36(3):1602.e17-27. Epub 2014 Oct 31 PubMed.

    View all comments by Julie van der Zee
  2. Interesting study. We had shown a few years ago that mutant huntingtin protein also increased turnover of profilin. Restoring profilin levels was sufficient to improve the disease phenotype. Of course back then we had no clue of the downstream effects of profilin loss outside of altered actin dynamics. Looks like we should dust off those old reagents and take another look at what regulates profilin turnover.


    . Expression of expanded polyglutamine targets profilin for degradation and alters actin dynamics. Neurobiol Dis. 2008 Jun;30(3):365-74. Epub 2008 Mar 6 PubMed.

    View all comments by Barrington Burnett

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  1. Mutations Open Cavity in Profilin, Destabilize the ALS-Linked Protein