Mutations in the <i>FUS/TLS</i> Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis

TLDR

Amyotrophic lateral sclerosis is a fatal motor neuron disease, with about 10 % of cases inherited and involving largely unknown genes, and pathogenic mechanisms include neuronal cytoplasmic protein aggregation and defective RNA metabolism. We identified 13 FUS/TLS mutations on chromosome 16 that cause familial ALS, with mutant proteins aggregating in neuronal cytoplasm, mirroring TDP43 pathology and supporting shared pathogenic mechanisms.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.