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Juvenile Amyotrophic Lateral Sclerosis (JALS) is a rare, early-onset form of ALS defined by motor neuron degeneration before 25 years of age. Heterozygous mutations in the RNA-binding protein FUS have emerged as the most common genetic cause of JALS, often presenting with rapidly progressive upper and lower motor neuron dysfunction (PMID:22248478). The spectrum of FUS variants in JALS includes missense, nonsense, frameshift, and splice-site changes clustering in the extreme C-terminus, a region critical for nuclear localization and RNA processing.
Genetic evidence for the FUS–JALS association is extensive. Over 20 unrelated probands harboring de novo or inherited FUS variants have been reported across multiple cohorts, including a novel 1-bp deletion leading to p.Arg495GlyfsTer27 (PMID:22248478), the recurrent p.Pro525Leu missense variant in aggressive JALS (PMID:27123482), and frameshift mutations in exon 14 identified in a Chinese JALS series (4/12 patients with FUS variants; 2 de novo) (PMID:28429524). A multicenter screen of 16 JALS patients found FUS mutations in 7 individuals, reinforcing its predominance among JALS genes (PMID:36801857). The absence of FUS mutations in familial segregation apart from isolated cases and the high de novo occurrence underline its autosomal dominant, often sporadic, presentation.
Inheritance of FUS-related JALS follows an autosomal dominant pattern, with most pathogenic alleles arising de novo. Familial segregation is limited, with only two multiplex JALS pedigrees reported and one unaffected carrier (PMID:22248478). No additional affected relatives carrying segregating FUS variants have been documented, indicating low penetrance or embryonic lethality in unaffected carriers.
Functional studies substantiate the pathogenicity of FUS C-terminal mutations. ALS-linked truncations and missense mutants, such as R495X, mislocalize to the cytoplasm and incorporate into stress granules upon cellular stress, unlike wild-type FUS (PMID:20699327). Deletion of the FUS nuclear localization signal disrupts nuclear import, leading to cytoplasmic accumulation and stress granule formation, implicating perturbed RNA metabolism in disease pathogenesis.
In vivo modeling in zebrafish demonstrates that both loss and gain of mutant FUS function impair neuromuscular junction transmission and motor behavior, supporting a dual mechanism of toxicity (PMID:23771027). Moreover, human iPSC-derived motor neurons carrying de novo p.Gly504ArgfsTer13 exhibit abnormal FUS aggregation, reduced electrophysiological activity, and transcriptional dysregulation, providing a platform for drug screening (PMID:33093822).
Mechanistically, FUS mutations confer a toxic gain-of-function through cytoplasmic mislocalization and stress granule sequestration of wild-type FUS, combined with partial loss of nuclear functions in RNA splicing and transcription regulation. These convergent effects culminate in motor neuron vulnerability manifesting as early-onset, rapidly progressive ALS.
Collectively, the robust genetic and experimental evidence supports a Definitive gene-disease association between FUS and Juvenile Amyotrophic Lateral Sclerosis. Clinical sequencing of FUS should be prioritized in patients with JALS for accurate diagnosis, prognosis, and genetic counselling.
Key take-home: FUS variants reliably predict an aggressive juvenile ALS phenotype, enabling targeted genetic testing and informing therapeutic development.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong23 probands with diverse FUS C-terminal variants in independent studies reaching genetic evidence cap Functional EvidenceModerateIn vitro stress granule and nuclear‐localization assays, zebrafish NMJ models, and patient iPSC neurons demonstrate pathogenic mechanisms |