FUS
FUS RNA Binding Protein
Gene Summary
RefSeq / NCBIThis gene encodes a multifunctional protein component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex. The hnRNP complex is involved in pre-mRNA splicing and the export of fully processed mRNA to the cytoplasm. This protein belongs to the FET family of RNA-binding proteins which have been implicated in cellular processes that include regulation of gene expression, maintenance of genomic integrity and mRNA/microRNA processing. Alternative splicing results in multiple transcript variants. Defects in this gene result in amyotrophic lateral sclerosis type 6. [provided by RefSeq, Sep 2009]
Clinical Phenotype
Familial ALS (FUS-ALS) and FTD-FUS. FUS-ALS typically has very early onset (teens to 30s) with rapid progression. Often presents with flail arm or flail leg syndrome. FUS mutations account for ~4% of fALS.
Molecular Mechanism
FUS (Fused in Sarcoma) is an RNA-binding protein involved in transcription, pre-mRNA splicing, and mRNA transport. ALS mutations impair nuclear import (disrupting PY-NLS interaction with Transportin-1), causing cytoplasmic mislocalization and stress granule incorporation, leading to toxic aggregates.
Clinical Hallmarks & Key Evidence
FUS-ALS uniquely features cytoplasmic FUS inclusions (not TDP-43), and pathology is absent from TDP-43 IHC — a key pathological distinction from the majority of ALS cases.
Kwiatkowski TJ Jr et al. Science. 2009;323(5918):1205-8.
Juvenile-onset ALS (before age 25) is disproportionately caused by FUS mutations — any young ALS patient should trigger urgent FUS genetic testing and family assessment.
Conte A et al. J Neurol Neurosurg Psychiatry. 2012;83(3):328-30.
Arginine methylation of FUS (by PRMT1) regulates its nuclear/cytoplasmic partitioning; arginine-to-cysteine mutations abolish methylation and maximally mislocalise FUS — correlating with the most aggressive phenotypes.
Dormann D et al. Nature. 2010;467(7311):729-33.
Associated Conditions
External Resources
Gene data compiled from the Washington University Neuromuscular Disease Center, NCBI Gene, and OMIM. For clinical use, always refer to primary sources.