Identification of novel disease relevant genetic modifiers affecting the SHH pathway in the developing brain

biorxiv(2020)

引用 0|浏览4
暂无评分
摘要
Pathogenic gene variants in humans affecting the sonic hedgehog (SHH) pathway lead to severe brain malformations with variable penetrance due to unknown genetic modifiers. To identify such modifiers, we established novel congenic mouse models. LRP2 deficient C57BL/6N mice suffer from heart outflow tract defects and holoprosencephaly caused by impaired SHH activity. These defects are fully rescued on FVB/N background indicating a strong influence of modifier genes. Applying comparative transcriptomics, we identified Pttg1 and Ulk4 as candidate modifiers upregulated in the rescue strain. Functional analyses showed that ULK4 and PTTG1, both microtubule-associated proteins, are new positive regulators of SHH signaling, rendering the pathway more resilient to disturbances. In addition, we characterized PTTG1 as a novel primary cilia component in the neuroepithelium. The identification of genes, that powerfully modulate the penetrance of genetic disturbances affecting the brain and heart, is likely relevant to understand variability in human congenital disorders. ### Competing Interest Statement The authors have declared no competing interest.
更多
查看译文
关键词
shh pathway,novel disease,relevant genetic modifiers
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要