Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA.
InVivo Biosystems, Eugene, OR 97402, USA.
Dis Model Mech. 2023 Aug 1;16(8). doi: 10.1242/dmm.050076. Epub 2023 Aug 29.
Hereditary spastic paraplegia (HSP) is a group of degenerative neurological disorders. We identified a variant in human kinesin light chain 4 (KLC4) that is suspected to be associated with autosomal-dominant HSP. How this and other variants relate to pathologies is unknown. We created a humanized Caenorhabditis elegans model in which klc-2 was replaced by human KLC4 (referred to as hKLC4) and assessed the extent to which hKLC4 retained function in the worm. We observed a slight decrease in motility but no nuclear migration defects in the humanized worms, suggesting that hKLC4 retains much of the function of klc-2. Five hKLC4 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 C. elegans as an animal model for HSP and to use it to test the significance of five variants of uncertain significance in the human gene KLC4.
遗传性痉挛性截瘫（HSP）是一组退行性神经疾病。我们在人类驱动蛋白轻链 4（KLC4）中发现了一个变异体，该变异体疑似与常染色体显性遗传性痉挛性截瘫有关。目前尚不清楚这种变异体以及其他变异体与病理学的关系。我们创建了一个人源化秀丽隐杆线虫模型，在该模型中klc-2 被人类 KLC4（称为 hKLC4）取代，并评估了 hKLC4 在蠕虫中保留功能的程度。我们观察到人源化蠕虫的运动能力略有下降，但没有核迁移缺陷，这表明 hKLC4保留了 klc-2 的大部分功能。将五个 hKLC4 变体引入人源化模型。临床变异体导致早期致死，纯合子时核迁移缺陷显著，杂合子时核迁移缺陷较弱，这可能与先证者杂合子时 HSP 的晚发临床发现相关。因此，我们能够建立人源化秀丽隐杆线虫作为 HSP 的动物模型，并使用它来测试人类 KLC4 基因中五个不确定意义变体的意义。
