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.

Novel mutations support a role for Profilin 1 in the pathogenesis of ALS / B.N. Smith, C. Vance, E.L. Scotter, C. Troakes, C.H. Wong, S. Topp, S. Maekawa, A. King, J.C. Mitchell, K. Lund, A. Al-Chalabi, N. Ticozzi, V. Silani, P. Sapp, R.H. Brown, J.E. Landers, S. Al-Sarraj, C.E. Shaw. - In: NEUROBIOLOGY OF AGING. - ISSN 0197-4580. - 36:3(2015 Mar), pp. 1602.e17-1602.e27.

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

N. Ticozzi;V. Silani;
2015

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.
Amyotrophic lateral sclerosis; Profilin 1; TDP-43 proteinopathy
Settore MED/26 - Neurologia
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
Settore MED/03 - Genetica Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/251941
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