Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
FUS encodes an RNA/DNA-binding protein whose heterozygous mutations cause an autosomal dominant juvenile-onset amyotrophic lateral sclerosis subtype (ALS6). Clinical presentation includes progressive muscle weakness, bulbar and respiratory failure, and variable features such as neck flexor weakness and myoclonic jerks. Pathogenic variants cluster in the C-terminal nuclear localization signal (PY-NLS) and include nonsense, missense, frameshift, splice, and 3′UTR alleles.
A total of 174 unrelated ALS6 probands (173 in a systematic review [PMID:37926865] and 1 juvenile case [PMID:30879340]) have been reported with heterozygous FUS variants, with no evidence of autosomal recessive inheritance and no common founder alleles. Functional studies uniformly show disrupted nuclear import and cytoplasmic accumulation of mutant FUS. Overall association strength: Strong.
Inheritance is autosomal dominant. No consanguinity reported; segregation has been observed in multiple affected family members but precise counts are unavailable. Reported variant spectrum includes missense (e.g., p.Pro525Leu), nonsense and frameshift (e.g., c.1483C>T (p.Arg495Ter) ([PMID:30879340])) and splice-site alleles. A comprehensive review identified 173 ALS cases with FUS mutations, highlighting allelic heterogeneity and early onset (mean age 35.2 ± 1.3 years) ([PMID:37926865]).
Mechanism: toxic gain-of-function via impaired nuclear localization, stress granule assembly, and RNA metabolism defects. Key assays include nuclear import binding studies of FUS-NLS/Transportin, stress granule colocalization in cell models and zebrafish, and rescue experiments in morpholino knockdowns. Mutant FUS shows decreased transportin affinity correlating with disease severity, cytoplasmic aggregation under stress, and neuronal toxicity in vivo.
No studies have refuted FUS-ALS6 association, though phenotypic variability exists. No alternative non-ALS phenotypes are consistently linked to FUS variants pathogenic for ALS6.
Heterozygous FUS variants demonstrate strong clinical validity for autosomal dominant ALS6, supported by extensive case series and concordant functional models. Genetic testing for FUS mutations is essential for diagnostic confirmation, prognosis, and familial counseling.
Key Take-home: FUS pathogenic variants cause a highly penetrant autosomal dominant juvenile ALS subtype, with genetic and functional data supporting routine clinical testing.
Gene–Disease AssociationStrong174 probands across multiple unrelated cases with heterozygous FUS variants; concordant functional data Genetic EvidenceStrong175 unrelated ALS6 probands with diverse heterozygous FUS variants including nonsense, missense, frameshift and splice; reached genetic cap Functional EvidenceModerateMultiple in vitro and in vivo models demonstrate impaired nuclear import, stress granule formation, and neuronal toxicity consistent with human ALS6 phenotype |