Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases
Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases
复制标题
DOI：
10.1007/s00401-019-02109-6
复制
发表时间：
2020-03-01
影响因子：
12.7
通讯作者：
Barakat, Tahsin Stefan
中科院分区：
文献类型：
--
作者：
Perenthaler, Elena;Nikoncuk, Anita;Barakat, Tahsin Stefan
发育性脑病和/或癫痫性脑病 (DEE) 是一组破坏性遗传性疾病，可导致早发、难治性癫痫发作和发育迟缓。在此，我们报告了来自 15 个家庭的 22 名患者，他们患有严重的顽固性癫痫、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。全外显子组测序在所有先证者的必需 UDP-葡萄糖焦磷酸化酶 (UGP2) 基因中发现了反复出现的纯合变异 (chr2:64083454A > G)。这种罕见的变异会导致较长 UGP2 蛋白异构体发生可容忍的 Met12Val 错义变化，但会导致较短异构体的起始密码子被破坏，而较短异构体在大脑中占主导地位。我们发现，较短亚型的缺失会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、未折叠蛋白反应上调和神经元过早分化，正如体外多能干细胞分化过程中所模拟的那样。相比之下，完全缺乏所有 UGP2 同工型会导致人类细胞多个谱系的分化缺陷。斑马鱼体内 Ugp2a/Ugp2b 表达的减少模拟了视觉障碍，而突变动物则表现出行为表型。我们的研究确定 UGP2 中反复出现的起始密码子突变是导致新型常染色体隐性 DEE 综合征的原因。重要的是，它还表明，导致必需蛋白质的组织相关同工型表达丧失的同工型特异性起始缺失突变可能导致遗传疾病，即使生物体范围内的蛋白质缺失与生命不相容。我们提供了适用类似疾病机制的其他示例。
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.