A humanizedCaenorhabditis elegansmodel of Hereditary Spastic Paraplegia-associated variants in kinesin light chain KLC4

Abstract

AbstractHereditary spastic paraplegia (HSP) is a group of degenerative neurological disorders. We identified a variant in human kinesin light chainKLC4that is suspected to be associated with autosomal dominant HSP. How this and other variants relate to pathologies is unknown. We created a humanizedC. elegansmodel whereklc-2 was replaced with humanKLC4and assessed the extent to whichhKLC4retained function in the worm. We observed a slight decrease in motility but no nuclear migration defects in the humanized worms, suggesting thathKLC4retains much of the function ofklc-2. FivehKLC4variants were introduced into the humanized model. The clinical variant led to early lethality with significant defects in nuclear migration when homozygous, and a weak nuclear migration defect when heterozygous, possibly correlating with the clinical finding of late onset HSP when the proband was heterozygous. Thus, we were able to establish humanizedC. elegansas an animal model for HSP and use it to test the significance of five variants of uncertain significance in the human geneKLC4.Summary StatementWe identified a variant inKLC4associated with Hereditary Spastic Paraplegia. The variant had physiological relevance in a humanizedC. elegansmodel where we replacedklc-2with humanKLC4.