Cohesin complex-associated holoprosencephaly
Cohesin complex-associated holoprosencephaly
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DOI：
10.1093/brain/awz210
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发表时间：
2019-09-01
期刊：
影响因子：
14.5
通讯作者：
Muenke, Maximilian
中科院分区：
文献类型：
--
作者：
Kruszka, Paul;Berger, Seth, I;Muenke, Maximilian
前脑无裂畸形是人类最常见的发育障碍之一，其特征是胚胎前脑的不完全分裂。尽管数十年的表型驱动的研究，80-90%的非整倍体阴性前脑无裂畸形的个人与可能的遗传病因没有遗传诊断。在这里，我们报告与X连锁的粘附素复合体基因，STAG 2和SMC 1A，在10个人和一个错义变异的功能丧失的变体的变体相关的前脑无裂畸形。此外，我们报告了四个人的变种，在cohesin复合体基因，不是X连锁，SMC 3和RAD 21。使用整体原位杂交，我们表明，STAG 2和SMC 1A在小鼠的前脑神经褶皱在初级神经形成，前脑形态发生和无前脑畸形的发病机制相一致。最后，我们发现STAG 2和SMC 1A的shRNA敲低导致人神经干细胞中HPE相关基因ZIC 2、GLI 2、SMAD 3和FGFR 1的异常表达。这些发现表明，cohesin复合物作为一个重要的调节器的中前脑发育和X连锁遗传模式的前脑无裂畸形。
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.