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Neurobiol Aging. 2015 Mar;36(3):1602.e17-27. doi: 10.1016/j.neurobiolaging.2014.10.032. Epub 2014 Oct 31.

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

Author information

1
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
2
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano - "Dino Ferrari" Centre, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
3
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
4
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK. Electronic address: Christopher.shaw@kcl.ac.uk.

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+/- 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.

KEYWORDS:

Amyotrophic lateral sclerosis; Profilin 1; TDP-43 proteinopathy

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