Three missense variants of ST3GAL3 are known to be responsible for a congenital disorder of glycosylation determining a neurodevelopmental disorder (intellectual disability/epileptic encephalopathy). Here we report a novel nonsense variant, p.Y220*, in two dichorionic infant twins presenting a picture of epileptic encephalopathy with impaired neuromotor development. Upon expression in HEK-293T cells, the variant appears totally devoid of enzymatic activity in vitro, apparently accumulated with respect to the wild-type or the missense variants, as detected by western blot, and in large part properly localized in the Golgi apparatus, as assessed by confocal microscopy. Both patients were found to efficiently express the CA19.9 antigen in the serum despite the total loss of ST3GAL3 activity, which thus appears replaceable from other ST3GALs in the synthesis of the sialyl-Lewis a epitope. Kinetic studies of ST3GAL3 revealed a strong preference for lactotetraosylceramide as acceptor and gangliotetraosylceramide was also efficiently utilized in vitro. Moreover, the p.A13D missense variant, the one maintaining residual sialyltransferase activity, was found to have much lower affinity for all suitable substrates than the wild-type enzyme with an overall catalytic efficiency almost negligible. Altogether the present data suggest that the apparent redundancy of ST3GALs deduced from knock-out mouse models only partially exists in humans. In fact, our patients lacking ST3GAL3 activity synthesize the CA19.9 epitope sialyl-Lewis a, but not all glycans necessary for fine brain functions, where the role of minor gangliosides deserves further attention.

中文翻译：

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在两个患有严重癫痫症并表达循环CA19.9的婴儿兄弟姐妹中，ST3GAL3的新型无意义和失活变体。

已知ST3GAL3的三种错义变异体与先天性糖基化疾病有关，后者决定了神经发育疾病（智力障碍/癫痫性脑病）。在这里，我们报告了一个新的无意义的变体，p.Y220 *，出现在两个双绒毛婴儿双胞胎中，呈现出癫痫性脑病与神经运动发育受损的情况。在HEK-293T细胞中表达后，该变体在体外似乎完全没有酶促活性，通过Western印迹检测到，相对于野生型或错义变体而言明显积累，并且在很大程度上正确定位于高尔基体中，通过共聚焦显微镜评估。尽管ST3GAL3活性完全丧失，但两名患者均在血清中有效表达CA19.9抗原，因此，在唾液酸化-刘易斯表位的合成中，它似乎可以被其他ST3GAL取代。ST3GAL3的动力学研究表明，强烈希望使用乳酸四糖基神经酰胺作为受体，神经节四糖基神经酰胺也可以在体外得到有效利用。而且，发现p.A13D错义变体，即一种保持残余唾液酸转移酶活性的变体，与所有野生型酶相比，对所有合适的底物的亲和力都低得多，总体催化效率几乎可以忽略不计。总的来说，目前的数据表明，从敲除小鼠模型推导出的ST3GAL的表观冗余仅部分存在于人类中。实际上，我们缺乏ST3GAL3活性的患者会合成CA19.9表位唾液酸化-刘易斯a，但不是大脑功能良好所需的所有聚糖，