Abstract:
Abstract 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+/-FTD cases including those identified in this report was significant p=0.001, OR=3.26 (95% CI 1.6-6.8), demonstrating this variant to be a susceptibility allele. Post-mortem tissue from available patients displayed classic TDP-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.
