Down syndrome (DS) is a gene-dosage disorder caused by the presence of all or part of a third copy of chromosome 21 (Hsa21). DS is associated with different complex phenotypes, including congenital heart disease (CHD), but the causes of heart defects are unclear. A new study used a previously described mouse model of DS (Dp1Tyb mice) that recapitulates key features of DS and develops CHD to provide new insights into the genetic causes of heart defects in DS. Using a systematic genetic mapping approach on the Dp1Tyb mice that carry an extra copy of ̴62% of the Hsa21-orthologous mouse genes, the researchers were able to identify Dyrk1a as one of the causative genes for CHD. In Dp1Tyb embryos, reducing the Dyrk1a gene copy number from three to two rescued heart defects, suggesting that DYRK1A may be a useful therapeutic target for treating CHD in patients with DS.

Original reference: Lana-Elola, E. et al. Sci. Transl. Med. 16, eadd6883 (2024)

唐氏综合症 (DS) 是一种因 21 号染色体第三个拷贝 (Hsa21) 的全部或部分存在而引起的基因剂量紊乱。 DS 与不同的复杂表型相关，包括先天性心脏病 (CHD)，但心脏缺陷的原因尚不清楚。一项新研究使用了先前描述的 DS 小鼠模型（Dp1Tyb 小鼠），该模型概括了 DS 的关键特征并发展为 CHD，为 DS 心脏缺陷的遗​​传原因提供了新的见解。研究人员对携带 Hsa21 直系同源小鼠基因额外副本 62% 的 Dp1Tyb 小鼠使用系统性遗传作图方法，确定Dyrk1a是 CHD 的致病基因之一。在 Dp1Tyb 胚胎中，将Dyrk1a基因拷贝数从 3 个减少到 2 个可挽救心脏缺陷，这表明 DYRK1A 可能是治疗 DS 患者先心病的有用治疗靶点。

原始参考文献： Lana-Elola, E. et al.科学。译。医学。 16 、eadd6883 (2024)