Abstract
BackgroundNeural tube defects (NTDs) are among the most common and severe congenital defects in humans. Their genetic etiology is complex and remains poorly understood. The Mediator complex (MED) plays a vital role in neural tube development in animal models. However, no studies have yet examined the role of its human homolog in the etiology of NTDs.MethodsIn this study, 48 pairs of neural lesion site and umbilical cord tissues from NTD and 21 case-parent trios were involved in screening for NTD-related somatic and germline de novo variants. A series of functional cell assays were performed. We generated a Med12 p.Arg1784Cys knock-in mouse using CRISPR/Cas9 technology to validate the human findings.ResultsOne somatic variant, MED12 p.Arg1782Cys, was identified in the lesion site tissue from an NTD fetus. This variant was absent in any other normal tissue from different germ layers of the same case. In 21 case-parent trios, one de novo stop-gain variant, MED13L p.Arg1760∗, was identified. Cellular functional studies showed that MED12 p.Arg1782Cys decreased MED12 protein level and affected the regulation of MED12 on the canonical-WNT signaling pathway. The Med12 p.Arg1784Cys knock-in mouse exhibited exencephaly and spina bifida.ConclusionThese findings provide strong evidence that functional variants of MED genes are associated with the etiology of some NTDs. We demonstrated a potentially important role for somatic variants in the occurrence of NTDs. Our study is the first study in which an NTD-related variant identified in humans was validated in mice using CRISPR/Cas9 technology.
Highlights
Neural tube defects (NTDs) are severe congenital defects caused by the failure of proper neural tube closure during early embryonic development
We validated one heterozygous somatic variant of Mediator complex subunit 12 (MED12) c.5344C > T (p.Arg1782Cys) in the lesion site tissue of a terminated female fetus diagnosed with craniorachischisis (Figure 1A)
We provided the first human evidence demonstrating that MED12 and Mediator complex subunit 13-like (MED13L) are associated with an increased risk for human NTDs
Summary
Neural tube defects (NTDs) are severe congenital defects caused by the failure of proper neural tube closure during early embryonic development. This group of malformations includes anencephaly, spina bifida, craniorachischisis, and encephalocele (Wallingford et al, 2013). There are well over 300 naturally occurring, induced, or targeted mutations in murine genes that have been reported to be associated with NTD phenotypes This no doubt contributes to the potential complexity of the underlying NTD genetics (Harris and Juriloff, 2007). Neural tube defects (NTDs) are among the most common and severe congenital defects in humans Their genetic etiology is complex and remains poorly understood. No studies have yet examined the role of its human homolog in the etiology of NTDs
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have