KIF5A – Amyotrophic Lateral Sclerosis

Kinesin family member 5A (KIF5A) encodes the neuron-specific heavy chain A of kinesin, a microtubule motor essential for anterograde axonal transport. Heterozygous variants in the C-terminal cargo-binding domain of KIF5A have been implicated in autosomal dominant amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder of upper and lower motor neurons ([PMID:29342275]).

Initial evidence came from a case–control analysis of 426 familial ALS patients and 6,137 controls, which demonstrated enrichment of splice-site mutations in exon 27 in ALS (2/426 vs 0/6,137; P = 4.2×10⁻³) and co-segregation of two canonical splice-site variants in independent pedigrees, implicating haploinsufficiency as the underlying mechanism ([PMID:29342275]).

A large kindred study reported a heterozygous missense variant c.3020G>A (p.Arg1007Lys) segregating with disease in 11 affected relatives, further substantiating the gene–disease link and illustrating phenotypic overlap with spastic paraplegia and Charcot–Marie–Tooth features ([PMID:36604770]).

Additional case reports have identified C-terminal tail missense variants, including c.2341A>G (p.Lys781Glu) in an atypical motor syndrome with mixed ALS–HSP presentation ([PMID:30583522]), and the canonical splice acceptor c.2993-1G>A in a Chinese sporadic ALS cohort (1/645, 0.16%) ([PMID:30301576]).

The variant spectrum extends from loss-of-function splice-site alleles to missense substitutions in diverse populations, with recurrent hotspot mutations in exon 27 and nearby residues across cohorts, confirming a consistent role of KIF5A in ALS pathogenesis.

Functional studies demonstrate a toxic gain-of-function mechanism for ΔExon27 mutants, which relieve autoinhibition, form aggregates, and impair neuronal survival in cell and Drosophila models ([PMID:35385738]; [PMID:35735139]). A CRISPR-Cas9 knock-in mouse carrying the murine homolog of an ALS-associated splice variant (c.3005+1G>A) shows delayed motor unit recovery after injury and progressive motor unit loss with aging, reflecting impaired maintenance and repair ([PMID:37164288]).

Collectively, genetic and experimental concordance establish KIF5A as a strong, autosomal dominant cause of ALS. Clinical testing for KIF5A variants supports diagnosis, genetic counseling, and eligibility for emerging targeted therapies.

References

• Brain | 2018 | Hot-spot KIF5A mutations cause familial ALS. PMID:29342275
• Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration | 2023 | Expanding the spectrum of KIF5A mutations-case report of a large kindred with familial ALS and overlapping syndrome. PMID:36604770
• Journal of Clinical Medicine | 2018 | A Novel Mutation in the Stalk Domain of KIF5A Causes a Slowly Progressive Atypical Motor Syndrome. PMID:30583522
• Neurobiology of Aging | 2019 | Mutation analysis of KIF5A in Chinese amyotrophic lateral sclerosis patients. PMID:30301576
• Cell Reports | 2022 | ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function. PMID:35385738
• EMBO Reports | 2022 | ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain-of-function. PMID:35735139
• Neurobiology of Disease | 2023 | Impaired motor unit recovery and maintenance in a knock-in mouse model of ALS-associated Kif5a variant. PMID:37164288

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