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Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a ubiquitously expressed RNA-binding protein that regulates pre-mRNA splicing, mRNA stability, and stress granule assembly in neurons and glia. It contains a prion-like low-complexity domain (LCD) essential for reversible protein fibrillization and stress response. ALS-linked mutations cluster in this LCD, perturbing hnRNPA1 dynamics and leading to cytoplasmic aggregation. Initial identification arose from whole-exome sequencing in two Chinese pedigrees with flail arm syndrome, an atypical ALS variant. Subsequent multi-patient studies and reviews have expanded the mutation spectrum to 15 distinct alleles across 27 ALS cases. This summary reviews genetic and functional data substantiating a definitive role for HNRNPA1 in amyotrophic lateral sclerosis.
Dominant inheritance is supported by two multigenerational families segregating the recurrent c.1018C>T (p.Pro340Ser) variant with complete penetrance in affected members ([PMID:36314424]; [PMID:27694260]). Beyond these pedigrees, targeted screening in 207 ALS patients identified three additional rare HNRNPA1 alleles ([PMID:38717009]). Overall, 27 unrelated probands harbored heterozygous missense or stop-loss variants in HNRNPA1, consistent with an autosomal dominant pattern and fulfilling strong genetic case-level criteria.
The variant spectrum includes primarily missense changes within the LCD (e.g., p.Asp314Val, p.Pro340Ser) and rare stop-loss extensions (e.g., p.Phe372_Ter373insTyrLeuGlyAsnLysAla). Recurrent p.Pro340Ser was observed in two independent ALS families manifesting flail arm syndrome with prolonged survival. Phenotypes range from classical limb-onset ALS to regional upper limb predominance, reflecting significant intra- and interfamilial heterogeneity. No clear founder effect has been established, and population screening indicates an overall mutation frequency below 1.5% in ALS cohorts.
Functional assays demonstrate mutation-specific effects on hnRNPA1 behavior. The p.Pro288Ser and p.Asp314Val variants accelerate fibrillization and slow stress granule disassembly, whereas p.Pro340Ser promotes cytoplasmic mislocalization and inclusion formation that colocalize with stress granule markers ([PMID:34291734]; [PMID:36314424]). Patient muscle biopsy corroborates cytoplasmic accumulation of hnRNPA1 aggregates. Cellular models show impaired stress granule clearance, consistent with a toxic gain-of-function mechanism contributing to motor neuron degeneration.
Large ALS and MSP/FTLD cohorts reveal that HNRNPA1 mutations are rare outside of familial ALS, with no pathogenic variants detected in multisystem proteinopathy or frontotemporal dementia without ALS features ([PMID:24119545]; [PMID:29131108]). This low frequency underlines allelic heterogeneity and possible reduced penetrance, but does not preclude clinical testing in familial or atypical ALS presentations.
Integration of robust segregation in two pedigrees, 27 probands with pathogenic variants, and concordant functional data meets ClinGen strong evidence thresholds for HNRNPA1 in ALS. Additional studies have explored diverse pathomechanisms but have not yet reached a quantitative cap. Key take-home: HNRNPA1 mutations represent a validated autosomal dominant cause of ALS, meriting inclusion in diagnostic gene panels and informing personalized therapeutic strategies.
Gene–Disease AssociationStrong27 ALS patients with 15 distinct HNRNPA1 mutations spanning two segregating pedigrees; segregation in multigenerational families and concordant functional studies Genetic EvidenceStrong27 probands with HNRNPA1 mutations including recurrent c.1018C>T (p.Pro340Ser); cosegregation in two families Functional EvidenceModerateIn vitro stress granule, fibrillization, and cellular localization assays show mutation-specific gain-of-function consistent with ALS |