Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by microtia, primordial dwarfism, small ears and skeletal abnormalities. Patients with MGS often carry mutations in genes encoding the subunits of the Origin Recognition Complex (ORC), components of the pre-replicative complex (pre-RC) and replication machinery. Orc6 is an important component of ORC and has functions in both DNA replication and cytokinesis. A mutation in the conserved C-terminal motif of Orc6 associated with MGS impedes the interaction of Orc6 with core ORC. Recently, a new mutation in Orc6 was also identified however, it is localized in the N-terminal domain of the protein. In order to study the functions of Orc6 we used the human gene to rescue the orc6 deletion in Drosophila Using this "humanized" Orc6-based Drosophila model of the Meier-Gorlin syndrome we discovered that unlike the previous Y225S MGS mutation in Orc6, the K23E substitution in the N-terminal TFIIB-like domain of Orc6 disrupts the protein ability to bind DNA. Our studies revealed the importance of evolutionarily conserved and variable domains of Orc6 protein and allowed the studies of human protein functions and the analysis of the critical amino acids in live animal heterologous system as well as provided novel insights into the mechanisms underlying MGS pathology.

中文翻译：

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Meier-Gorlin 综合征的人源化果蝇模型揭示了 Orc6 蛋白的保守和差异特征。

Meier-Gorlin 综合征 (MGS) 是一种罕见的常染色体隐性遗传疾病，其特征为小耳症、原始侏儒症、小耳朵和骨骼异常。MGS 患者通常携带编码起源识别复合体 (ORC) 亚基、预复制复合体 (pre-RC) 和复制机制的组成部分的基因突变。Orc6是ORC的重要组成部分，具有DNA复制和胞质分裂的功能。与 MGS 相关的 Orc6 保守 C 端基序的突变阻碍了 Orc6 与核心 ORC 的相互作用。最近，Orc6 中还发现了一个新的突变，但它位于蛋白质的 N 末端结构域。为了研究 Orc6 的功能，我们使用人类基因来拯救果蝇中的orc6缺失。使用这种“人源化”的基于 Orc6的 Meier-Gorlin 综合征果蝇模型，我们发现与之前 Orc6 中的 Y225S MGS 突变不同，K23E Orc6 N 端 TFIIB 样结构域的取代会破坏蛋白质结合 DNA 的能力。我们的研究揭示了 Orc6 蛋白进化上保守和可变结构域的重要性，并允许研究人类蛋白质功能和分析活体动物异源系统中的关键氨基酸，并为 MGS 病理学机制提供新的见解。