Department of Neurology; Wellstone Center for FSHD
Genetics and Genomics | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology
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 ( approximately 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.
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Citation: Neurobiol Aging. 2015 Mar;36(3):1602.e17-27. doi: 10.1016/j.neurobiolaging.2014.10.032. Epub 2014 Oct 31. Link to article on publisher's site
Smith, Bradley N.; Vance, Caroline; Scotter, Emma L.; Troakes, Claire; Wong, Chun Hao; Topp, Simon; Maekawa, Satomi; King, Andrew; Mitchell, Jacqueline C.; Lund, Karan; Al-Chalabi, Ammar; Ticozzi, Nicola; Silani, Vincenzo; Sapp, Peter; Brown, Robert H. Jr.; Landers, John E.; Al-Sarraj, Safa; and Shaw, Christopher E., "Novel mutations support a role for Profilin 1 in the pathogenesis of ALS" (2015). Wellstone Center for FSHD Publications and Presentations. 30.
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