Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis


Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years1,2,3,4,5,6,7,8,9, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.

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Figure 1: Exome sequencing identifies PFN1 gene mutations in familial ALS.
Figure 2: Mutant PFN1 produces ubiquitinated insoluble aggregates.
Figure 3: Mutant PFN1 inhibits axon outgrowth.
Figure 4: Mutant PFN1 reduces growth cone size and F/G-actin expression.


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Support was provided by the ALS Therapy Alliance, Project ALS, P2ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation and a Francesco Caleffi donation (N.T. and V.S.). Grant support was provided by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) (1R01NS065847 (J.E.L.), 1R01NS050557 (R.H.B.), and RC2-NS070-342 (R.H.B.)), Muscular Dystrophy Association (MDA173851 (W.R.)) and AriSLA co-financed with support of ‘5x1000’—Healthcare research of the Ministry of Health (EXOMEFALS (N.T., C.G., V.S. and J.E.L.)). Support was provided by an SMA Europe fellowship to C.F. P.C.S. was supported through the auspices of H. R. Horvitz (Massachusetts Institute of Technology), an investigator of the Howard Hughes Medical Institute. We thank the laboratory of S. Doxsey, the UMass Medical School Digital Light Microscopy Core, the UMass Medical School Deep Sequencing Core, the Emory University Neuropathology Core, and M. Gearing and D. Cooper for their assistance.

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Sample collection, preparation and clinical evaluation: N.T., P.C.S., D.M.-Y., F.T., C.T., J.D.G., G.S., F.S., V.M., A.R., C.G., V.S., V.E.D., R.H.B. Performed experiments and data analysis: C.-H.W., C.F., N.T., P.J.K., P.C.S., K.P., P.L., D.M.B., J.E.K., P.G.-P., A.D.F., M.K., J.A., F.T., C.T., A.L.L., S.C.C., E.T.C., D.A.B., J.E.L. Scientific planning and direction: C.-H.W., C.F., N.T., D.M., M.J.M., J.A.Z., Z.-S.X., L.H.V, J.D.G., D.B.G., V.M., W.R., A.R., C.G., D.A.B., G.J.B., V.S., V.E.D., R.H.B., J.E.L. Initial manuscript preparation: C.-H.W., C.F., N.T., W.R., D.A.B., G.J.B., V.S., R.H.B., J.E.L.

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Correspondence to John E. Landers.

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Wu, CH., Fallini, C., Ticozzi, N. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499–503 (2012).

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