Mutations in the <i>KIF5A</i> N-terminal motor domain are known to cause SPG10; An autosomal dominant hereditary spastic paraplegia (HSP), as well as rare Charcot-Marie-Tooth disease 2 (CMT2) cases.
We performed in vitro assays on dimeric recombinant Kif5A with HSP-causing mutations in the Switch I domain, which participates in the coordination and hydrolysis of ATP by kinesin.
Variants in SPAST and KIF5A were the most common causes of autosomal dominant HSP, whereas SPG11 and CYP7B1 were the most common cause of autosomal recessive HSP.
KIF5A mutations have been associated with a wide clinical spectrum, ranging from pure HSP to isolated peripheral nerve involvement or complicated HSP phenotypes.
By combining next-generation sequencing and conventional sequencing, we confirm that KIF5A mutations can cause variable phenotypes ranging from HSP to CMT2.
SPG10 is a rare form of autosomic dominant hereditary spastic paraplegia (HSP) caused by mutations in the KIF5A gene, which may be involved in axonal transport.
By comparing the phenotypes and the complementation behaviors of a large set of Khc missense alleles, including one that is identical to a human Kif5AHSP allele, we identified three routes to suppression of Khc phenotypes: nutrient restriction, genetic background manipulation, and a remarkable intramolecular complementation between mutations known or likely to cause reciprocal changes in the rate of microtubule-stimulated ADP release by kinesin-1.
Spastic paraplegia type 10 (SPG10) is an autosomal dominant form of hereditary spastic paraplegia (HSP) due to mutations in KIF5A, a gene encoding the neuronal kinesin heavy chain implicated in anterograde axonal transport.
SPG10 mutations were found in 10% of our complicated forms of HSP, suggesting that mutations in KIF5A represent the major cause of complicated AD-HSP in France.
The negative result obtained in 15 patients without mutations in SPG4 in whom 4 other genes were analyzed (SPG3A, SPG6, SPG10, and SPG13) indicate that these genes are not frequently mutated in sporadic pure HSP.
We report a four-generation pedigree segregating an autosomal dominant phenotype for HSP and showing a linkage to the SPG10 locus, coding for Kinesin family member 5A.