Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
Brain. 2019 Sep 1;142(9):2631-2643. doi: 10.1093/brain/awz210.
Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.
脑裂畸形是一种常见的人类发育障碍，其特征是胚胎前脑不完全分裂。尽管数十年来一直进行表型驱动的研究，但仍有 80-90%的非整倍体阴性、可能具有遗传病因的无脑裂畸形患者未得到基因诊断。在这里，我们报告了与两个 X 连锁黏合复合物基因 STAG2 和 SMC1A 相关的无脑裂畸形，在 10 个个体中存在功能丧失性变异，在 1 个个体中存在错义变异。此外，我们还报告了 4 个存在非 X 连锁黏合复合物基因 SMC3 和 RAD21 变异的个体。通过全胚胎原位杂交，我们显示 STAG2 和 SMC1A 在小鼠初级神经胚形成过程中在前脑神经褶中表达，与前脑形态发生和无脑裂畸形发病机制一致。最后，我们发现 STAG2 和 SMC1A 的 shRNA 敲低导致人类神经干细胞中与 HPE 相关的基因 ZIC2、GLI2、SMAD3 和 FGFR1 的异常表达。这些发现表明黏合复合物是脑裂畸形中中脑发育和 X 连锁遗传模式的重要调节因子。
