Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6

TLDR

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease, with 10 % familial cases, and mutations in the RNA‑processing protein FUS—known to regulate transcription, RNA splicing, and transport—have been implicated, suggesting a shared pathogenic mechanism with TARDBP. A survey of 197 familial ALS index cases identified two additional missense mutations in FUS across eight families, highlighting its role in transcription, RNA splicing, and transport. We identified a missense FUS mutation linked to ALS6, and postmortem and cellular studies revealed FUS‑immunoreactive cytoplasmic inclusions, predominant lower motor neuron degeneration, and aberrant mutant protein localization.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.