KIF5A – Autosomal Dominant Hereditary Spastic Paraplegia

Kinesin family member 5A (KIF5A; HGNC:6323) encodes the neuronal kinesin heavy chain required for fast anterograde axonal transport. Heterozygous KIF5A mutations underlie SPG10, an autosomal dominant form of hereditary spastic paraplegia (HSP), manifesting as progressive lower-limb spasticity with or without peripheral neuropathy (PMID:15452312; PMID:21107874).

Extensive case series and population screens have identified KIF5A variants in multiple unrelated HSP families. A four-generation pedigree segregating a c.838C>T (p.Arg280Cys) variant demonstrated co-segregation in five affected relatives (PMID:15452312). Italian screening of 139 AD-HSP probands revealed five distinct motor-domain missense variants in 5 probands (PMID:21623771), while a European cohort found three novel mutations in 3/80 families (3.8%) (PMID:18245137). In total, at least 16 unrelated probands harbor KIF5A mutations, reaching ClinGen genetic scoring thresholds.

Variants are predominantly missense changes clustered in the motor domain, with the recurrent hotspot c.838C>T (p.Arg280Cys). These alter conserved residues involved in microtubule binding and ATP hydrolysis, while occasional stalk-domain and tail variants expand the spectrum of phenotypes.

Clinically, KIF5A-related HSP presents as a pure spastic paraplegia (HP:0001258) often accompanied by subclinical or overt peripheral axonal neuropathy (HP:0003477), dysautonomia, or deafness. Age at onset ranges from infancy to adulthood with high penetrance in AD families.

Functional studies demonstrate that HSP-associated KIF5A motor mutants (N256S, K253N, R280C) exhibit reduced microtubule affinity, gliding velocity, and processivity, with dominant-negative inhibition of cargo transport in vitro (PMID:18203753). Structural modeling corroborates impaired stepping and dimerization defects in exon-27 mutants.

Integration of genetic and functional data supports a definitive gene–disease relationship underpinned by haploinsufficiency and dominant-negative mechanisms. KIF5A testing should be included in diagnostic panels for autosomal dominant HSP and CMT2 with pyramidal signs. Key take-home: KIF5A mutations cause SPG10 via impaired axonal transport, enabling precise genetic diagnosis and guiding therapeutic research.

References

• Neurology • 2004 • Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. PMID:15452312
• Neurological sciences • 2011 • A novel mutation in KIF5A gene causing hereditary spastic paraplegia with axonal neuropathy. PMID:21107874
• Clinical genetics • 2012 • Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2. PMID:21623771
• Journal of neurology, neurosurgery, and psychiatry • 2008 • SPG10 is a rare cause of spastic paraplegia in European families. PMID:18245137
• Human molecular genetics • 2008 • Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity. PMID:18203753

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