In-depth analysis reveals complex molecular aetiology in a cohort of idiopathic cerebral palsy.
In-depth analysis reveals complex molecular aetiology in a cohort of idiopathic cerebral palsy.
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深入分析揭示了特发性脑性瘫痪队列中复杂的分子病因。
DOI：
10.1093/brain/awab209
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发表时间：
2022-03-29
期刊：
影响因子：
--
通讯作者：
Hu H
中科院分区：
文献类型：
--
作者：
Li N;Zhou P;Tang H;He L;Fang X;Zhao J;Wang X;Qi Y;Sun C;Lin Y;Qin F;Yang M;Zhang Z;Liao C;Zheng S;Peng X;Xue T;Zhu Q;Li H;Li Y;Liu L;Huang J;Liu L;Peng C;Kaindl AM;Gecz J;Han D;Liu D;Xu K;Hu H
脑性瘫痪是儿童中最常见的身体残疾;然而，其内在的分子机制仍不清楚。在本研究中，我们对120个特发性脑瘫家族进行了深入的临床和分子分析，并在45%的患者中发现了潜在的有害遗传变异。除了生殖系变异，我们还发现了约6.7%的脑瘫患者存在疾病相关的合子后突变。我们发现，有更严重运动障碍或智力残疾合并症的患者有更高的机会携带疾病相关的变异。通过汇编114个已知的脑瘫相关基因，我们确定了遗传和功能方面的特征，根据这些基因的表达模式和相关的认知障碍，我们提出了一个二分分类系统。在两名脑瘫和智力残疾的患者中，我们发现缺陷TYW 1，一种tRNA超修饰酶，通过阻碍神经元增殖和迁移引起原发性小头畸形和运动和认知问题。此外，我们开发了一种算法，并在小鼠大脑中证明，这种功能失调的超修饰特别干扰了参与细胞周期的蛋白质子集的翻译。这一发现为先天性小头畸形提供了一个新的有趣的机制。在另一名智力正常的脑瘫患者中，我们发现了一种线粒体酶GPAM，其亚型形式导致人类和小鼠模型中皮质脊髓束的髓鞘形成不足。此外，我们证实，异常的Gpam在小鼠中扰乱了星形胶质细胞的脂质代谢，导致星形胶质细胞增殖抑制和少突胶质细胞髓鞘形成的脂质含量不足。总之，我们的研究结果阐明了脑瘫病因学的新方面，并为未来的治疗策略提供了见解。Li等人对120个脑瘫家庭进行了深入的遗传和临床分析。他们在54个家族中发现了有害的遗传变异，包括两个以前与脑瘫无关的基因：TYW 1和GPAM。功能研究揭示了这些基因分别在神经发生和髓鞘形成中的作用。
Cerebral palsy is the most prevalent physical disability in children; however, its inherent molecular mechanisms remain unclear. In the present study, we performed in-depth clinical and molecular analysis on 120 idiopathic cerebral palsy families, and identified underlying detrimental genetic variants in 45% of these patients. In addition to germline variants, we found disease-related postzygotic mutations in ∼6.7% of cerebral palsy patients. We found that patients with more severe motor impairments or a comorbidity of intellectual disability had a significantly higher chance of harbouring disease-related variants. By a compilation of 114 known cerebral-palsy-related genes, we identified characteristic features in terms of inheritance and function, from which we proposed a dichotomous classification system according to the expression patterns of these genes and associated cognitive impairments. In two patients with both cerebral palsy and intellectual disability, we revealed that the defective TYW1, a tRNA hypermodification enzyme, caused primary microcephaly and problems in motion and cognition by hindering neuronal proliferation and migration. Furthermore, we developed an algorithm and demonstrated in mouse brains that this malfunctioning hypermodification specifically perturbed the translation of a subset of proteins involved in cell cycling. This finding provided a novel and interesting mechanism for congenital microcephaly. In another cerebral palsy patient with normal intelligence, we identified a mitochondrial enzyme GPAM, the hypomorphic form of which led to hypomyelination of the corticospinal tract in both human and mouse models. In addition, we confirmed that the aberrant Gpam in mice perturbed the lipid metabolism in astrocytes, resulting in suppressed astrocytic proliferation and a shortage of lipid contents supplied for oligodendrocytic myelination. Taken together, our findings elucidate novel aspects of the aetiology of cerebral palsy and provide insights for future therapeutic strategies. Li et al. present an in-depth genetic and clinical analysis of 120 families with cerebral palsy. They identify detrimental genetic variants in 54 families, including in two genes not previously associated with cerebral palsy: TYW1 and GPAM. Functional studies reveal roles for these genes in neurogenesis and myelination, respectively.
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影响因子：
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作者：
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