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

摘要： 唐氏综合征（DS），由21三体（T21）引起，有许多相关的缺陷，一个标志是100- 先天性巨结肠症（HSCR或先天性结肠无神经节细胞症）的风险增加一倍。的机理 关联是难以捉摸的，但一个关键的线索是，一个常见的RET增强子变异，与非 综合征HSCR也与DS伴HSCR病例相关，但与DS不伴HSCR病例无关。这些数据表明 这种关联是由于21号染色体（HSA 21）基因的剂量增加导致RET-EDNRB失调， 基因调控网络（GRN）增加HSCR风险，这一机制可能解释其他DS性状。一 特异性HSA 21候选物是SOD 1，一种假定的RET负调节物，其可以进一步降低RET 在具有RET缺陷增强子等位基因的DS病例中表达。此外，非整倍体特异性蛋白质失衡 也可以影响细胞增殖和HSCR。在这里，我们提出了研究人类遗传学的三个目标， 工程化多能干细胞（iPSC）和HSA 21基因和RET的小鼠模型中的功能基因组学， 了解HSA 21基因特异性和T21特异性遗传效应导致HSCR的机制- 相关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.