CFAP410 – Amyotrophic Lateral Sclerosis

Systematic sequencing of 44 ALS-relevant genes in 100 patients revealed rare CFAP410 variants in a subset of cases (PMID:33589474). In a regional cohort of 150 ALS patients, 13 individuals (8.7%) harboured the common missense allele c.172G>T (p.Val58Leu) in CFAP410, suggesting an increased risk contribution (PMID:37159497). No segregation of these variants in families has been reported.

Functional analysis of the p.Val58Leu substitution demonstrates enhanced NEK1-mediated hyperphosphorylation, impaired FBXO3-dependent ubiquitination, stabilization of mutant CFAP410–NEK1 complexes, and significant neurite outgrowth defects in motor neuron models (PMID:32891887). These findings support a gain-of-function mechanism disrupting proteostasis and neuronal maintenance. Further family-based and population studies are required to establish definitive Mendelian inheritance and penetrance.

Key take-home: CFAP410 is a candidate ALS risk gene with moderate functional evidence, meriting inclusion in expanded diagnostic panels.

References

• Journal of neurology, neurosurgery, and psychiatry • 2021 • Value of systematic genetic screening of patients with amyotrophic lateral sclerosis PMID:33589474
• iScience • 2020 • An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO3 PMID:32891887

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