Novel mutations support a role for Profilin 1 in the pathogenesis of ALS

Bradley N. Smith, Caroline Vance, Emma L. Scotter, Claire Troakes, Chun Hao Wong, Simon Topp, Satomi Maekawa, Andrew King, Jacqueline C. Mitchell, Karan Lund, Ammar Al-Chalabi, Nicola Ticozzi, Vincenzo Silani, Peter Sapp, Robert H. Brown, John E. Landers, Safa Al-Sarraj, Christopher E. Shaw

Research output: Contribution to journalArticlepeer-review


Mutations in the gene encoding profilin 1 (PFN1) have recently been shown to cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. We sequenced the PFN1 gene in a cohort of ALS patients (n= 485) and detected 2 novel variants (A20T and Q139L), as well as 4 cases with the previously identified E117G rare variant (~ 1.2%). A case-control meta-analysis of all published E117G ALS+/- frontotemporal dementia cases including those identified in this report was significant p= 0.001, odds ratio= 3.26 (95% confidence interval, 1.6-6.7), demonstrating this variant to be a susceptibility allele. Postmortem tissue from available patients displayed classic TAR DNA-binding protein 43 pathology. In both transient transfections and in fibroblasts from a patient with the A20T change, we showed that this novel PFN1 mutation causes protein aggregation and the formation of insoluble high molecular weight species which is a hallmark of ALS pathology. Our findings show that PFN1 is a rare cause of ALS and adds further weight to the underlying genetic heterogeneity of this disease.

Original languageEnglish
Pages (from-to)1602.e17-e27
JournalNeurobiology of Aging
Issue number3
Publication statusPublished - Mar 1 2015


  • Amyotrophic lateral sclerosis
  • Profilin 1
  • TDP-43 proteinopathy

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology


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