title: Novel mutations support a role for Profilin 1 in the pathogenesis of ALS.
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.
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Smith
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Scotter
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Chun Hao
authors.initials: CH
authors.lastname: Wong
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Topp
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Satomi
authors.initials: S
authors.lastname: Maekawa
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Mitchell
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Karan
authors.initials: K
authors.lastname: Lund
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.affiliation: 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.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ticozzi
authors.affiliation: 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.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Sapp
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.affiliation: 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.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
mesh_terms: D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D009154:Mutation / Q000235:genetics*; D051304:Profilins / Q000235:genetics*; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D051304:Profilins
keywords: Amyotrophic lateral sclerosis; Profilin 1; TDP-43 proteinopathy