Dystonia is a debilitating hyperkinetic movement disorder, frequently transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense and missense variants in TSPOAP1, encoding the active zone RIM-binding protein 1 (RIMBP1), as a novel genetic cause of autosomal recessive dystonia in seven subjects from three unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between presynaptic RIMBP1 dysfunction and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

中文翻译：

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编码活性区蛋白RIMBP1的TSPOAP1中的双等位基因变异导致常染色体隐性肌张力障碍

肌张力障碍是一种使人衰弱的运动亢进症，经常以单基因性状传播。在这里，我们描述TSPOAP1中的纯合移码，无义和错义变体，编码活性区RIM结合蛋白1（RIMBP1），作为来自三个无关家庭的七个受试者的常染色体隐性肌张力障碍的新型遗传原因。携带功能丧失型变异的受试者表现为少年发作性进行性全身肌张力障碍，与智力障碍和小脑萎缩有关。相反，携带病原体错义变体（p.Gly1808Ser）的受试者表现为孤立的成人发作局灶性肌张力障碍。在小鼠中，RIMBP1的完全丧失（已知会减少神经传递）导致运动异常，让人联想到肌张力障碍，浦肯野细胞树突状树突减少，并减少小脑突触的数量。对p.Gly1808Ser变体的体外分析显示，较大的峰值诱发钙瞬变和增强的神经传递，表明RIMBP1相关性肌张力障碍可能是由相关神经网络中的峰值诱发释放速率降低或升高引起的。我们的发现建立了突触前RIMBP1功能障碍和肌张力障碍之间的直接联系，并突出了神经平衡传递在运动控制和疾病发病机理中的关键作用。