PFN1 – Amyotrophic Lateral Sclerosis

Profilin 1 (PFN1) is definitively associated with autosomal dominant amyotrophic lateral sclerosis (MONDO:0004976). Exome sequencing in two large familial ALS pedigrees identified four PFN1 missense mutations in 7 of 274 FALS cases (p.Cys71Gly, p.Met114Thr, p.Gly118Val, p.Glu117Gly) and segregation of p.Gly118Val with disease (PMID:22801503). Subsequent screening across US, Nordic, and German cohorts of 412 familial and 260 sporadic ALS patients identified a novel p.Thr109Met mutation that co‐segregated with ALS in a German family and the p.Glu117Gly variant in another pedigree, both absent in controls (PMID:23141414). A Bulgarian pedigree spanning three generations and four affected relatives carried a heterozygous p.Val31Gly variant with complete segregation (PMID:36846111).

PFN1 mutations display a clear dominant inheritance pattern with at least five additional affected relatives demonstrating co‐segregation. To date, >10 unrelated probands have been reported carrying pathogenic PFN1 missense changes, predominantly affecting the actin‐binding and poly‐proline‐binding interfaces (e.g., c.326C>T (p.Thr109Met)) and manifesting as spinal‐onset motor neuron disease without cognitive involvement. The p.Glu117Gly allele occurs in both cases and controls and likely represents a moderate risk susceptibility variant rather than a fully penetrant mutation (PMID:24309268).

Mechanistic and experimental studies consistently support a gain-of-toxic-function model. Mutant PFN1 proteins form ubiquitinated, insoluble aggregates sequestering TDP-43, impede axon outgrowth, and disrupt cytoskeletal dynamics in neuronal cultures. Transgenic Drosophila and mouse models expressing PFN1 Cys71Gly or Thr109Met develop progressive motor neuron degeneration, PFN1 aggregation, ubiquitin/p62 pathology, and impaired muscle strength (PMID:27681617). Structural analyses reveal mutation-induced destabilization of PFN1’s core, increasing aggregation propensity and perturbing actin and microtubule regulation (PMID:26056300).

No substantial conflicting evidence disputes the causality of canonical PFN1 mutations in ALS; however, the p.Glu117Gly variant shows lower pathogenicity and is considered a risk allele. Overall, genetic, segregation, and multi-model functional data robustly support a Strong gene–disease association.

Key Take-home: PFN1 should be included in ALS diagnostic gene panels for its autosomal dominant mutations that cause a spinal‐onset ALS phenotype.

References

• Nature • 2012 • Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. PMID:22801503
• Neurobiology of Aging • 2013 • A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts. PMID:23141414
• Frontiers in Neurology • 2023 • Novel variant c.92T > G (p.Val31Gly) in the PFN1 gene (ALS18) responsible for a specific phenotype in a large Bulgarian amyotrophic lateral sclerosis pedigree. PMID:36846111
• Journal of Neurology, Neurosurgery, and Psychiatry • 2014 • Profilin1 E117G is a moderate risk factor for amyotrophic lateral sclerosis. PMID:24309268

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