FUS – Amyotrophic Lateral Sclerosis

FUS encodes a ubiquitously expressed RNA/DNA-binding protein involved in RNA splicing, transport, and DNA repair. Heterozygous pathogenic variants in FUS cause autosomal dominant amyotrophic lateral sclerosis (ALS), characterized by progressive upper and lower motor neuron degeneration, muscle weakness, and eventual respiratory failure. Clinically, FUS-ALS often has early onset, rapid progression, frequent bulbar involvement, and de novo mutation occurrences. Molecularly, disease-causing variants cluster in the C-terminal nuclear localization signal (PY-NLS), leading to nuclear import defects and cytoplasmic mislocalization.

Genetic Evidence

FUS-ALS follows an autosomal dominant inheritance pattern. To date, >173 unrelated probands with FUS variants have been reported in ALS cohorts ([PMID:37926865]). Segregation of pathogenic FUS alleles has been confirmed in at least 11 multiplex families ([PMID:20577002]). The mutational spectrum includes missense (e.g., p.Arg521Cys, p.Pro525Leu), nonsense, frameshift, and splice‐site variants, with de novo and familial cases. A recurrent variant is c.1574C>T (p.Pro525Leu), associated with juvenile onset and aggressive disease courses.

Experimental Evidence

Mechanistically, C-terminal PY-NLS mutations abrogate Transportin-mediated nuclear import, resulting in cytoplasmic accumulation and incorporation of mutant FUS into stress granules under cellular stress ([PMID:20699327]). Structural studies of the FUS-NLS/Transportin complex reveal that ALS-linked mutations weaken binding affinity by up to 700-fold, correlating with mislocalization and disease severity ([PMID:23056579]). In zebrafish models, mutant FUS expression impairs neuromuscular junction transmission and motor behavior, supporting a toxic gain-of-function mechanism.

Integration & Clinical Utility

The convergence of extensive case series, familial segregation, and concordant functional studies establishes a definitive gene-disease relationship between FUS and ALS. Genetic testing for FUS variants is critical for early diagnosis, prognostic stratification, and genetic counseling.

Key Take-Home

Autosomal dominant FUS mutations are a definitive cause of ALS6; screening in early-onset or familial ALS improves diagnostic yield and informs clinical management.

References

• Amyotrophic lateral sclerosis & Frontotemporal Degeneration • 2024 • FUS gene mutation in amyotrophic lateral sclerosis: a new case report and systematic review PMID:37926865
• Journal of medical genetics • 2010 • SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations PMID:20577002
• Human Molecular Genetics • 2010 • Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules PMID:20699327
• PLoS One • 2012 • FUS-NLS/Transportin 1 complex structure provides insights into the nuclear targeting mechanism of FUS and the implications in ALS PMID:23056579

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