Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.

中文翻译：

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UGP2在大脑中的丧失会导致严重的癫痫性脑病，强调必需基因的双等位基因同工型特异性起始丢失突变会导致遗传疾病。

发育性和/或癫痫性脑病（DEE）是一组毁灭性的遗传疾病，导致早期发作，抗药性癫痫发作和发育延迟。在这里，我们报告了来自15个家庭的22名个体，这些个体表现为严重形式的顽固性癫痫，严重的发育迟缓，进行性小头畸形，视力障碍和类似的轻微畸形。整个外显子组测序在所有先证者中的必需UDP-葡萄糖焦磷酸化酶（UGP2）基因中鉴定出一个复发性纯合变异体（chr2：64083454A> G）。这种罕见的变体导致较长的UGP2蛋白同工型的Met12Val错义变化可忍受，但会导致较短的同工型的起始密码子中断，而该起始密码子在大脑中占主导地位。我们显示，较短的同工型的缺乏导致神经干细胞中功能性UGP2酶的减少，从而导致糖原代谢改变，未折叠的蛋白质反应上调和神经元过早分化，如在体外多能干细胞分化中所模拟的那样。相反，完全缺乏所有UGP2同工型会导致人类细胞中多个谱系的分化缺陷。斑马鱼体内Ugp2a / Ugp2b的表达减少模仿了视觉障碍，突变动物表现出行为表型。我们的研究发现UGP2中的起始密码子重复突变是新型常染色体隐性DEE综合征的病因。重要的是，它还表明，导致必需蛋白的组织相关同工型表达缺失的同工型特异性起始缺失突变可导致遗传病，即使全生物范围内的蛋白质缺失都与生命不相容。我们提供了适用类似疾病机制的其他示例。