Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.

中文翻译：

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netrin-1基因突变导致先天性镜像移动

Netrin-1是一种分泌蛋白，在20年前被首次鉴定为调节CNS中线杂交的轴突导向分子。它在整个发育过程中在各种组织中起关键作用，并与成年期的肿瘤发生和炎症有关。尽管进行了广泛的研究，但尚未有人类遗传病直接与编码netrin-1的基因NTN1中的突变直接相关。在这里，我们确定了2个无关家族中NTN1外显子7的3个突变和1例散发性先天性孤立镜子运动（CMM）的病例，这种疾病的特征是一只手的不自主运动反映了另一只手的故意运动。鉴于netrin-1的不同作用，在NTN1中没有CMM以外的其他表现形式突变携带者出乎意料。使用多模式方法，我们发现NTN1突变型CMM患者的皮质脊髓束（CST）解剖异常。当在HEK293或稳定的HeLa细胞中表达时，与WT netrin-1（在细胞内和细胞外隔室中均检测到）相反，几乎仅在细胞内隔室中检测到了3种突变的netrin-1蛋白。由于netrin-1是一种可扩散的细胞外信号，因此病理生理学可能涉及其功能丧失和随后的轴突导向破坏，从而导致CST异常转移。