Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive.,American Journal of Human Genetics

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Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2018-12-27 , DOI: 10.1016/j.ajhg.2018.11.018
Simon Edvardson ₁ , Claudia M Nicolae ₂ , Grace J Noh ₃ , Jennifer E Burton ₄ , Giuseppe Punzi ₅ , Avraham Shaag ₆ , Jessica Bischetsrieder ₃ , Anna De Grassi ₅ , Ciro Leonardo Pierri ₅ , Orly Elpeleg ₆ , George-Lucian Moldovan ₂

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Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates a stress response mechanism to clear out the unfolded proteins by either facilitating their re-folding or inducing their degradation. When this fails, an apoptotic cascade is initiated so that the affected cell is eliminated. IRE1α is a critical sensor of the unfolded-protein response, essential for initiating the apoptotic signaling. Here, we report an infantile neurodegenerative disorder associated with enhanced activation of IRE1α and increased apoptosis. Three unrelated affected individuals with congenital microcephaly, infantile epileptic encephalopathy, and profound developmental delay were found to carry heterozygous variants (c.932T>C [p.Leu311Ser] or c.935T>C [p.Leu312Pro]) inRNF13, which codes for an IRE1α-interacting protein. Structural modeling predicted that the variants, located on the surface of the protein, would not alter overall protein folding. Accordingly, the abundance of RNF13 and IRE1α was not altered in affected individuals’ cells. However, both IRE1α-mediated stress signaling and stress-induced apoptosis were increased in affected individuals’ cells. These results indicate that theRNF13variants confer gain of function to the encoded protein and thereby lead to altered signaling of the ER stress response associated with severe neurodegeneration in infancy.

中文翻译：

杂合RNF13功能获得性变异与先天性小头畸形，癫痫性脑病，失明和无法存活有关。

内质网（ER）中未折叠蛋白的积累启动了应激反应机制，通过促进其重新折叠或诱导其降解来清除未折叠的蛋白。如果失败，则会启动凋亡级联反应，从而消除受影响的细胞。IRE1α是未折叠蛋白应答的关键传感器，对于启动细胞凋亡信号转导至关重要。在这里，我们报告婴儿神经退行性疾病与IRE1α的增强激活和凋亡增加有关。发现三个不相关的先天性小头畸形，婴儿癫痫性脑病和严重发育延迟的受影响个体在RNF13中携带杂合变异体（c.932T> C [p.Leu311Ser]或c.935T> C [p.Leu312Pro]），其编码为IRE1α相互作用蛋白。结构模型预测，位于蛋白质表面的变体不会改变蛋白质的整体折叠。因此，在受影响的个体细胞中RNF13和IRE1α的丰度没有改变。然而，IRE1α介导的应激信号和应激诱导的细胞凋亡在受影响的个体细胞中均增加。这些结果表明，RNF13变体赋予编码的蛋白质功能增强，从而导致与婴儿期严重神经变性相关的ER应激反应的信号改变。IRE1α介导的应激信号和应激诱导的细胞凋亡均在受影响的个体细胞中增加。这些结果表明，RNF13变体赋予编码的蛋白质功能增强，从而导致与婴儿期严重神经变性相关的ER应激反应的信号改变。IRE1α介导的应激信号和应激诱导的细胞凋亡均在受影响的个体细胞中增加。这些结果表明，RNF13变体赋予编码的蛋白质功能增强，从而导致与婴儿期严重神经变性相关的ER应激反应的信号改变。

更新日期：2018-12-28

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