PDF(Pubmed)
Abstract：
EZH1, a polycomb repressive complex-2 component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3 lysine27 (H3K27) trimethylation (H3K27me3). Genetic variants in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease. However, the paralog EZH2 is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novo missense variant in EZH1 through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and an analogous somatic or germline mutation in EZH2 has been reported in patients with B-cell lymphoma or Weaver syndrome, respectively. Human EZH1/2 are homologous to fly Enhancer of zeste (E(z)), an essential gene in Drosophila, and the affected residue (p.A678 in humans, p.A691 in flies) is conserved. To further study this variant, we obtained null alleles and generated transgenic flies expressing wildtype [E(z)WT] and the variant [E(z)A691G]. When expressed ubiquitously the variant rescues null-lethality similar to the wildtype. Overexpression of E(z)WT induces homeotic patterning defects but notably the E(z)A691G variant leads to dramatically stronger morphological phenotypes. We also note a dramatic loss of H3K27me2 and a corresponding increase in H3K27me3 in flies expressing E(z)A691G, suggesting this acts as a gain-of-function allele. In conclusion, here we present a novel EZH1 de novo variant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in Drosophila.
摘要：
EZH1，一种多梳抑制复合物-2(PRC2)组分，参与了无数的细胞过程。EZH1通过组蛋白3lysine27(H3K27)三甲基化(H3K27me3)抑制下游靶基因的转录。组蛋白修饰剂的遗传变异与发育障碍有关，而EZH1尚未与任何人类疾病有关。然而,模拟EZH2与Weaver综合征相关。在这里，我们报告了一个以前未诊断的个体，具有一种新的神经发育表型，通过外显子组测序在EZH1中具有从头错义变异。该个体在婴儿期出现神经发育迟缓和张力减退，后来被发现具有近端肌肉无力。变种,p.A678G,在SET域中，以其甲基转移酶活性而闻名，在患有B细胞淋巴瘤或韦弗综合征的患者中，已经报道了EZH2的类似体细胞或种系突变，分别。人EZH1/2与zeste的果蝇增强子同源，E(z),果蝇的重要基因,和受影响的残留物（p。A678在人类中，果蝇中的p.A691）是保守的。为了进一步研究这种变体，我们获得了无效等位基因，并产生了表达野生型[E（z）WT]和变体[E（z）A691G]的转基因果蝇。当广泛表达时，该变体挽救了与野生型相似的无效致死性。E(z)WT的过表达诱导同源模式缺陷,但值得注意的是E(z)A691G变体导致显著更强的形态表型。我们还注意到在表达E(z)A691G的果蝇中H3K27me2的急剧损失和H3K27me3的相应增加。这表明这是一个获得功能的等位基因。总之,在这里，我们提出了一种与神经发育障碍相关的新的EZH1从头变异。此外，我们发现这种变异体对果蝇有功能性影响.
