Cargando…

Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects

BACKGROUND: Neural 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...

Descripción completa

Detalles Bibliográficos
Autores principales: Tian, Tian, Cao, Xuanye, Chen, Yongyan, Jin, Lei, Li, Zhiwen, Han, Xiao, Lin, Ying, Wlodarczyk, Bogdan J., Finnell, Richard H., Yuan, Zhengwei, Wang, Linlin, Ren, Aiguo, Lei, Yunping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969791/
https://www.ncbi.nlm.nih.gov/pubmed/33748132
http://dx.doi.org/10.3389/fcell.2021.641831
_version_ 1783666299158659072
author Tian, Tian
Cao, Xuanye
Chen, Yongyan
Jin, Lei
Li, Zhiwen
Han, Xiao
Lin, Ying
Wlodarczyk, Bogdan J.
Finnell, Richard H.
Yuan, Zhengwei
Wang, Linlin
Ren, Aiguo
Lei, Yunping
author_facet Tian, Tian
Cao, Xuanye
Chen, Yongyan
Jin, Lei
Li, Zhiwen
Han, Xiao
Lin, Ying
Wlodarczyk, Bogdan J.
Finnell, Richard H.
Yuan, Zhengwei
Wang, Linlin
Ren, Aiguo
Lei, Yunping
author_sort Tian, Tian
collection PubMed
description BACKGROUND: Neural 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. METHODS: In 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. RESULTS: One 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. CONCLUSION: These 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.
format Online
Article
Text
id pubmed-7969791
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-79697912021-03-19 Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects Tian, Tian Cao, Xuanye Chen, Yongyan Jin, Lei Li, Zhiwen Han, Xiao Lin, Ying Wlodarczyk, Bogdan J. Finnell, Richard H. Yuan, Zhengwei Wang, Linlin Ren, Aiguo Lei, Yunping Front Cell Dev Biol Cell and Developmental Biology BACKGROUND: Neural 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. METHODS: In 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. RESULTS: One 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. CONCLUSION: These 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. Frontiers Media S.A. 2021-03-04 /pmc/articles/PMC7969791/ /pubmed/33748132 http://dx.doi.org/10.3389/fcell.2021.641831 Text en Copyright © 2021 Tian, Cao, Chen, Jin, Li, Han, Lin, Wlodarczyk, Finnell, Yuan, Wang, Ren and Lei. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Tian, Tian
Cao, Xuanye
Chen, Yongyan
Jin, Lei
Li, Zhiwen
Han, Xiao
Lin, Ying
Wlodarczyk, Bogdan J.
Finnell, Richard H.
Yuan, Zhengwei
Wang, Linlin
Ren, Aiguo
Lei, Yunping
Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects
title Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects
title_full Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects
title_fullStr Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects
title_full_unstemmed Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects
title_short Somatic and de novo Germline Variants of MEDs in Human Neural Tube Defects
title_sort somatic and de novo germline variants of meds in human neural tube defects
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969791/
https://www.ncbi.nlm.nih.gov/pubmed/33748132
http://dx.doi.org/10.3389/fcell.2021.641831
work_keys_str_mv AT tiantian somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT caoxuanye somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT chenyongyan somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT jinlei somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT lizhiwen somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT hanxiao somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT linying somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT wlodarczykbogdanj somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT finnellrichardh somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT yuanzhengwei somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT wanglinlin somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT renaiguo somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects
AT leiyunping somaticanddenovogermlinevariantsofmedsinhumanneuraltubedefects