Ylikallio Emil, Kim Doyoun, Isohanni Pirjo, Auranen Mari, Kim Eunjoon, Lönnqvist Tuula, Tyynismaa Henna
Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea.
Eur J Hum Genet. 2015 Oct;23(10):1427-30. doi: 10.1038/ejhg.2014.297. Epub 2015 Jan 14.
Variants in family 1 kinesin (KIF1A), which encodes a kinesin axonal motor protein, have been described to cause variable neurological manifestations. Recessive missense variants have led to spastic paraplegia, and recessive truncations to sensory and autonomic neuropathy. De novo missense variants cause developmental delay or intellectual disability, cerebellar atrophy and variable spasticity. We describe a family with father-to-son transmission of de novo variant in the KIF1A motor domain, in a phenotype of pure spastic paraplegia. Structural modeling of the predicted p.(Ser69Leu) amino acid change suggested that it impairs the stable binding of ATP to the KIF1A protein. Our study reports the first dominantly inherited KIF1A variant and expands the spectrum of phenotypes caused by heterozygous KIF1A motor domain variants to include pure spastic paraplegia. We conclude that KIF1A should be considered a candidate gene for hereditary paraplegias regardless of inheritance pattern.
编码驱动蛋白轴突运动蛋白的1型驱动蛋白（KIF1A）中的变异已被描述为可导致多种神经系统表现。隐性错义变异导致痉挛性截瘫，隐性截短变异导致感觉和自主神经病变。新发错义变异导致发育迟缓或智力残疾、小脑萎缩和不同程度的痉挛。我们描述了一个家族，其中KIF1A运动结构域的新发变异从父亲传给儿子，表现为单纯性痉挛性截瘫。预测的p.(Ser69Leu)氨基酸变化的结构模型表明，它会损害ATP与KIF1A蛋白的稳定结合。我们的研究报告了首个显性遗传的KIF1A变异，并将杂合KIF1A运动结构域变异导致的表型谱扩展至包括单纯性痉挛性截瘫。我们得出结论，无论遗传模式如何，KIF1A都应被视为遗传性截瘫的候选基因。
