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首页> 外文期刊>The journal of clinical investigation >Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance
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Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance

机译：人类NSMCE2的亚同型与原始侏儒症和胰岛素抵抗有关

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Structural maintenance of chromosomes (SMC) complexes are essential for maintaining chromatin structure and regulating gene expression. Two the three known SMC complexes, cohesin and condensin, are important for sister chromatid cohesion and condensation, respectively; however, the function of the third complex, SMC5–6, which includes the E3 SUMO-ligase NSMCE2 (also widely known as MMS21) is less clear. Here, we characterized 2 patients with primordial dwarfism, extreme insulin resistance, and gonadal failure and identified compound heterozygous frameshift mutations in NSMCE2 . Both mutations reduced NSMCE2 expression in patient cells. Primary cells from one patient showed increased micronucleus and nucleoplasmic bridge formation, delayed recovery of DNA synthesis, and reduced formation of foci containing Bloom syndrome helicase (BLM) after hydroxyurea-induced replication fork stalling. These nuclear abnormalities in patient dermal fibroblast were restored by expression of WT NSMCE2, but not a mutant form lacking SUMO-ligase activity. Furthermore, in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE. Collectively, these findings support a role for NSMCE2 in recovery from DNA damage and raise the possibility that loss of its function produces dwarfism through reduced tolerance of replicative stress.
机译：染色体（SMC）复合物的结构维护对于维持染色质结构和调节基因表达至关重要。三种已知的SMC复合物中的两种，粘着素和凝缩素分别对姐妹染色单体的内聚和凝结很重要。但是，包含E3 SUMO连接酶NSMCE2（也被广泛称为MMS21）的第三个复合体SMC5-6的功能尚不清楚。在这里，我们鉴定了2例原发性侏儒症，极度胰岛素抵抗和性腺功能衰竭的患者，并确定了NSMCE2中的复合杂合性移码突变。两种突变均降低了患者细胞中NSMCE2的表达。一名患者的原代细胞显示出增加的微核和核质桥形成，延迟了DNA合成的恢复，并减少了羟基脲诱导的复制叉停滞后含有Bloom综合征解旋酶（BLM）的病灶的形成。 WT NSMCE2的表达恢复了患者皮肤成纤维细胞中的这些核异常，但缺少SUMO-连接酶活性的突变形式却没有恢复。此外，在斑马鱼中，敲低NSMCE2直系同源物会产生侏儒症，这种现象可通过WT的重新表达而得到缓解，但SUMO-连接酶缺陷的NSMCE不会被重新表达。总的来说，这些发现支持NSMCE2在从DNA损伤中恢复中的作用，并增加了其功能丧失通过降低复制压力的耐受性而产生侏儒症的可能性。

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