Loss of RAD9B impairs early neural development and contributes to the risk for human spina bifida.

TitleLoss of RAD9B impairs early neural development and contributes to the risk for human spina bifida.
Publication TypeJournal Article
Year of Publication2020
AuthorsCao X, Tian T, Steele JW, Cabrera RM, Aguiar-Pulido V, Wadhwa S, Bhavani N, Bi P, Gargurevich NH, Hoffman EN, Cai C-Q, Marini NJ, Yang W, Shaw GM, Ross ME, Finnell RH, Lei Y
JournalHum Mutat
Date Published2020 Jan 03

DNA damage response (DDR) genes orchestrating the network of DNA repair, cell cycle control, are essential for the rapid proliferation of neural progenitor cells. To date, the potential association between specific DDR genes and the risk of human neural tube defects (NTDs) has not been investigated. Using whole-genome sequencing and targeted sequencing, we identified significant enrichment of rare deleterious RAD9B variants in spina bifida cases compared to controls (8/409 vs. 0/298; pā€‰=ā€‰.0241). Among the eight identified variants, the two frameshift mutants and p.Gln146Glu affected RAD9B nuclear localization. The two frameshift mutants also decreased the protein level of RAD9B. p.Ser354Gly, as well as the two frameshifts, affected the cell proliferation rate. Finally, p.Ser354Gly, p.Ser10Gly, p.Ile112Met, p.Gln146Glu, and the two frameshift variants showed a decreased ability for activating JNK phosphorylation. RAD9B knockdowns in human embryonic stem cells profoundly affected early differentiation through impairing PAX6 and OCT4 expression. RAD9B deficiency impeded in vitro formation of neural organoids, a 3D cell culture model for human neural development. Furthermore, the RNA-seq data revealed that loss of RAD9B dysregulates cell adhesion genes during organoid formation. These results represent the first demonstration of a DDR gene as an NTD risk factor in humans.

Alternate JournalHum. Mutat.
PubMed ID31898828
Grant ListHD081216 / GF / NIH HHS / United States
HD074695 / GF / NIH HHS / United States
HD083809 / GF / NIH HHS / United States
CU01DD001033 / CC / CDC HHS / United States
HD067244 / GF / NIH HHS / United States
R01 HD074695 / HD / NICHD NIH HHS / United States