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

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 pre...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357530/
https://www.ncbi.nlm.nih.gov/pubmed/25499087
http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.032
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author 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.
author_facet 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.
author_sort Smith, Bradley N.
collection PubMed
description 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.
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spelling pubmed-43575302015-03-31 Novel mutations support a role for Profilin 1 in the pathogenesis of ALS 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. Neurobiol Aging Genetic Report 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. Elsevier 2015-03 /pmc/articles/PMC4357530/ /pubmed/25499087 http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.032 Text en Crown Copyright © Published by Elsevier Inc. All rights reserved. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Genetic Report Abstract
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.
Novel mutations support a role for Profilin 1 in the pathogenesis of ALS
title Novel mutations support a role for Profilin 1 in the pathogenesis of ALS
title_full Novel mutations support a role for Profilin 1 in the pathogenesis of ALS
title_fullStr Novel mutations support a role for Profilin 1 in the pathogenesis of ALS
title_full_unstemmed Novel mutations support a role for Profilin 1 in the pathogenesis of ALS
title_short Novel mutations support a role for Profilin 1 in the pathogenesis of ALS
title_sort novel mutations support a role for profilin 1 in the pathogenesis of als
topic Genetic Report Abstract
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357530/
https://www.ncbi.nlm.nih.gov/pubmed/25499087
http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.032
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