A humanized model of Hereditary Spastic Paraplegia-associated variants in kinesin light chain KLC4.

Unlabelled: Hereditary spastic paraplegia (HSP) is a group of degenerative neurological disorders. We identified a variant in human kinesin light chain that is suspected to be associated with autosomal dominant HSP. How this and other variants relate to pathologies is unknown. We created a humanized model where 2 was replaced with human and assessed the extent to which retained function in the worm. We observed a slight decrease in motility but no nuclear migration defects in the humanized worms, suggesting that retains much of the function of . Five variants 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 humanized as an animal model for HSP and use it to test the significance of five variants of uncertain significance in the human gene .

Summary Statement: We identified a variant in associated with Hereditary Spastic Paraplegia. The variant had physiological relevance in a humanized model where we replaced with human .