Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement.
Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement.
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DOI：
10.1016/j.ymgme.2019.12.013
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发表时间：
2020-03
影响因子：
3.8
通讯作者：
Van Hove JLK
中科院分区：
文献类型：
--
作者：
Friederich MW;Perez FA;Knight KM;Van Hove RA;Yang SP;Saneto RP;Van Hove JLK
白质疾病在遗传上是非常不同的，包括几个与线粒体生物能量学有关的基因。神经成像的模式识别和下一代测序有助于对潜在原因的诊断。最近，复杂的I装配因子NUBPL的遗传变化的特征是白质脑病的一致可识别的模式，影响到深部白质，包括胼胝体和小脑。在这里，我们报告了一对双等位基因变异的双胞胎男孩，一个未报道的c.351G>；A；p.(Met117Ile)和一个先前报道的病理变异c.693+1G>；A。脑磁共振成像显示异常T2高信号，累及脑室周围白质、外囊、胼胝体，尤其是双侧丘脑。18个月后，患者的神经影像表现为明显的弥漫性白质信号异常，体积减少，并在小脑叶状区和疣状区出现新的信号异常区域。磁共振波谱显示乳酸升高。在培养的成纤维细胞中的功能研究证实了这些基因变异的致病性。吸光光度法检测呼吸链复合体I活性缺乏，凝胶内活性染色显示蓝色天然凝胶上呼吸链复合体I活性缺失。当用NDUFS2抗体示踪时，络合物I的基质臂蛋白质没有组装和丢失，而当用NDUFB6抗体示踪时，膜臂不完全组装。免疫印迹显示，与对照组相比，患者成纤维细胞中的NUBPL蛋白减少。NUBPL活性受损损害了复合体I的基质臂的组装，并在MRI上产生了严重的、快速进行性的白质脑病，并累及丘脑，进一步扩大了神经影像表型。
Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum. Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G>A; p.(Met117Ile) and a previously reported pathological variant c. 693+1 G>A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate. Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls. Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.
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