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

• DOI: 10.1016/j.neurobiolaging.2014.10.032
• Publication Date: 2014-10-31T02:00:55Z
• Authors: Bradley N. Smith; Caroline Vance; Emma L. Scotter; Claire Troakes; Chun Hao Wong; Simon Topp; Satomi Maekawa; Andrew King; Jacqueline C. Mit...; Karan Lund; Ammar Al-Chalabi; Nicola Ticozzi; Vincenzo Silani; Peter Sapp; Robert H. Brown; John E. Landers; Safa Al-Sarraj; Christopher E. Shaw
• Keywords: Pathogenesis

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