Objective: To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models.

Methods: We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same amino acid position.

Results: A novel mutation c.1574C>G (p.525P>R) in the in the FUS gene was identified in the index patient. The clinical symptoms are similar to those in familial ALS patients with the P525L mutation at the same position. The P525R mutant FUS protein showed cytoplasmic localization and formed large stress granule–like cytoplasmic inclusions in multiple cellular models.

Conclusions: The clinical features of the patient and the cytoplasmic inclusions of the P525R mutant FUS protein strengthen the notion that mutations at position 525 of the FUS protein result in a coherent phenotype characterized by juvenile or young adult onset, rapid progression, variable positive family history, and female preponderance.

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Published in Neurology Genetics, v. 3, no. 4, p. 1-9.

© 2017 The Author(s).

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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Funding Information

This study was in part supported by the National Institutes of Neurological Disorder and Stroke grant R01NS077284, MDA grant MDA352743, ALS Association grant 6SE340 and VA MERIT award I01 BX002149 (to H.Z.), and Crispen and Heidrich endowments (to E.J.K.). The support from the Multidisciplinary Value Program (MVP) initiative in the University of Kentucky College of Medicine is appreciated. M.K. and A.A. are supported by the National Institute of Environmental Health Sciences training grant T32ES007266.

The Article Processing Charge was funded by the University of Kentucky.