Why do Down Syndrome patients have high risk of Hirschsprung disease?

摘要： 由21三体(T21)引起的唐氏综合征(DS)有许多相关的缺陷，其标志是100- 先天性巨结肠症(HSCR或先天性结肠神经节细胞缺乏症)的风险增加一倍。这其中的机制是 关联是难以捉摸的，但关键线索是一种常见的RET增强子变体，与非 综合征型HSCR也与伴有HSCR的DS病例有关，但与无HSCR的DS病例无关。这些数据表明 这种联系是因为21号染色体(HSA21)基因剂量增加，导致RET-EDNRB失调 基因调控网络(GRN)增加HSCR风险，这可能是解释其他DS特征的机制。一 特定的HSA21候选基因是SOD1，它可能是RET的负调控因子，可以进一步降低RET RET缺乏增强子等位基因在DS患者中的表达此外，非整倍体特有的蛋白质失衡 也会影响细胞增殖和HSCR。在这里，我们提出了研究人类遗传学的三个目标， HSA21基因和RET的工程多能干细胞和小鼠模型的功能基因组学， 为了了解HSA21基因特异性和T21特异性遗传效应导致HSCR的机制。 关联DS。

ABSTRACT: Down syndrome (DS), resulting from trisomy 21 (T21), has many associated defects, a hallmark being the 100- fold higher risk of Hirschsprung disease (HSCR or congenital colonic aganglionosis). The mechanism of this association is elusive, but a critical clue is that a common RET enhancer variant, associated with non- syndromic HSCR, is also associated with DS cases with HSCR but not DS cases without. These data suggest that the association is from increased dosage of chromosome 21 (HSA21) genes dysregulating the RET-EDNRB gene regulatory network (GRN) to increase HSCR risk, a mechanism likely explaining other DS traits. One specific HSA21 candidate is SOD1, a putative negative regulator of RET, that can further reduce RET expression in DS cases with RET deficiency enhancer alleles. Further, aneuploidy-specific protein imbalance can also affect cell proliferation and HSCR. Here, we propose three aims investigating human genetics, functional genomics in engineered pluripotent stem cells (iPSC) and mouse models of HSA21 genes and RET, to understand the mechanisms by which HSA21 gene-specific and T21-specific genetic effects lead to HSCR- associated DS.