To conduct a genetic and molecular functional study of a family with members affected of hereditary spastic paraplegia (HSP) of unknown origin and carrying a novel pathogenic vaccinia-related kinase 1 (VRK1) variant.

Whole-exome sequencing was performed in 2 patients, and their parents diagnosed with HSP. The novel VRK1 variant was detected by whole-exome sequencing, molecularly modeled and biochemically characterized in kinase assays. Functionally, we studied the role of this VRK1 variant in DNA damage response and its effect on the assembly of Cajal bodies (CBs).

We have identified a very rare homozygous variant VRK1-D263G with a neurologic phenotype associated with HSP and moderate intellectual disability. The molecular modeling of this VRK1 variant protein predicted an alteration in the folding of a loop that interferes with the access to the kinase catalytic site. The VRK1-D263G variant is kinase inactive and does not phosphorylate histones H2AX and H3, transcription factors activating transcription factor 2 and p53, coilin needed for assembly of CBs, and p53 binding protein 1, a DNA repair protein. Functionally, this VRK1 variant protein impairs CB formation and the DNA damage response.

This report expands the neurologic spectrum of neuromotor syndromes associated with a new and rare VRK1 variant, representing a novel pathogenic participant in complicated HSP and demonstrates that CBs and the DNA damage response are impaired in these patients.

对一个患有未知来源的遗传性痉挛性截瘫 (HSP) 并携带新的致病性牛痘相关激酶 1 ( VRK 1) 变体的家庭进行遗传和分子功能研究。

对 2 名患者进行了全外显子组测序，他们的父母被诊断为 HSP。新型VRK 1 变体通过全外显子组测序、分子建模和激酶测定中的生化特征进行检测。在功能上，我们研究了这种VRK 1 变体在 DNA 损伤反应中的作用及其对 Cajal 体 (CBs) 组装的影响。

我们已经确定了一种非常罕见的纯合变体 VRK1-D263G，其具有与 HSP 和中度智力障碍相关的神经表型。这种 VRK1 变体蛋白的分子模型预测了一个环折叠的改变，该改变干扰了对激酶催化位点的访问。VRK1-D263G 变体没有激酶活性，不会磷酸化组蛋白 H2AX 和 H3、激活转录因子 2 和 p53 的转录因子、组装 CB 所需的线圈和 p53 结合蛋白 1，一种 DNA 修复蛋白。在功能上，这种VRK1变体蛋白会损害 CB 的形成和 DNA 损伤反应。

本报告扩展了与一种新的和罕见的VRK1变体相关的神经运动综合征的神经学谱，代表了复杂 HSP 的新致病参与者，并证明这些患者的 CBs 和 DNA 损伤反应受损。