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

• Published in: Neurobiology of aging Vol. 36; no. 3; pp. 1602.e17 - 1602.e27
• Main Authors: 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., Landers, John E., Al-Sarraj, Safa, Shaw, Christopher E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2015; Elsevier
• Subjects: Alleles; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Animals; Case-Control Studies; Cells, Cultured; Cohort Studies; DNA-Binding Proteins - metabolism; Female; Genetic Association Studies; Genetic Predisposition to Disease - genetics; Genetic Report Abstract; Genetic Variation - genetics; Humans; Internal Medicine; Male; Meta-Analysis as Topic; Mutation - genetics; Neurology; Profilin 1; Profilins - genetics; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - pathology; TDP-43 proteinopathy; Profilin 1; Amyotrophic lateral sclerosis; TDP-43 proteinopathy
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2014.10.032

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.