KIF1A Associated Neurological Disorder (KAND) encompasses a recently identified group of rare neurodegenerative conditions caused by variants in KIF1A, a member of the kinesin-3 family of microtubule (MT) motor proteins. Here we characterize the natural history of KAND in 117 individuals using a combination of caregiver or self-reported medical history, a standardized measure of adaptive behavior, clinical records, and neuropathology. We developed a heuristic severity score using a weighted sum of common symptoms to assess disease severity. Focusing on 100 individuals, we compared the average clinical severity score for each variant with in silico predictions of deleteriousness and location in the protein. We found increased severity is strongly associated with variants occurring in regions involved with ATP and MT-binding: the P-loop, switch I, and switch II. For a subset of identified variants, we generated recombinant mutant proteins which we used to assess transport in vivo by assessing neurite tip accumulation, and to assess MT binding, motor velocity, and processivity using total internal reflection fluorescence microscopy. We find all patient variants result in defects in transport, and describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. The molecular rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced binding is associated with milder clinical phenotypes. Our findings suggest the clinical phenotypic heterogeneity in KAND likely reflects and parallels diverse molecular phenotypes. We propose a new way to describe KAND subtypes to better capture the breadth of disease severity.

中文翻译：

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基于微管运动的基因型和缺陷与KIF1A相关神经系统疾病的临床严重程度相关

KIF1A相关的神经系统疾病（KAND）涵盖了由KIF1A（微管（MT）运动蛋白的kinesin-3家族成员）中的变异引起的一组罕见的神经退行性疾病。在这里，我们通过结合照顾者或自我报告的病史，适应性行为，临床记录和神经病理学的标准化测量方法，对117个人中KAND的自然病史进行了表征。我们使用常见症状的加权总和得出启发式严重性评分，以评估疾病的严重性。针对100个个体，我们将每个变体的平均临床严重程度评分与该蛋白质的有害性和位置进行计算机预测。我们发现，严重程度的提高与发生在与ATP和MT结合有关的区域中的变异密切相关：P环，开关I，并切换II。对于已鉴定变体的子集，我们生成了重组突变蛋白，该蛋白用于通过评估神经突尖端积累来评估体内转运，并使用全内反射荧光显微镜来评估MT结合，运动速度和合成能力。我们发现所有患者变体均导致运输缺陷，并描述了三类蛋白质功能障碍：MT结合力降低，速度和合成能力降低，以及严格的MT结合力。严格的分子表型与最严重的临床表型始终相关，而结合减少则与较轻的临床表型相关。我们的发现表明，KAND中的临床表型异质性可能反映并平行了多种分子表型。