PDF(Pubmed)
Abstract：
Generalized lipodystrophy is a feature of various hereditary disorders, often leading to a progeroid appearance. In the present study we identified a missense and a frameshift variant in a compound heterozygous state in SUPT7L in a boy with intrauterine growth retardation, generalized lipodystrophy, and additional progeroid features. SUPT7L encodes a component of the transcriptional coactivator complex STAGA. By transcriptome sequencing, we showed the predicted missense variant to cause aberrant splicing, leading to exon truncation and thereby to a complete absence of SUPT7L in dermal fibroblasts. In addition, we found altered expression of genes encoding DNA repair pathway components. This pathway was further investigated and an increased rate of DNA damage was detected in proband-derived fibroblasts and genome-edited HeLa cells. Finally, we performed transient overexpression of wildtype SUPT7L in both cellular systems, which normalizes the number of DNA damage events. Our findings suggest SUPT7L as a novel disease gene and underline the link between genome instability and progeroid phenotypes.
摘要：
广义脂肪营养不良是各种遗传性疾病的特征，经常导致早衰的外观。在本研究中，我们在一名宫内发育迟缓的男孩的SUPT7L中发现了复合杂合状态的错义和移码变体，全身性脂肪营养不良，和额外的早衰特征。SUPT7L编码转录共激活子复合物STAGA的组分。通过转录组测序，我们显示了预测的错义变异导致异常剪接，导致外显子截短，从而在真皮成纤维细胞中完全不存在SUPT7L。此外,我们发现编码DNA修复途径组分的基因表达发生改变.进一步研究了该途径，并在先证者衍生的成纤维细胞和基因组编辑的HeLa细胞中检测到DNA损伤的增加率。最后,我们在两个细胞系统中进行了野生型SUPT7L的瞬时过表达，使DNA损伤事件的数量正常化。我们的发现表明SUPT7L是一种新的疾病基因，并强调了基因组不稳定性和早衰表型之间的联系。
