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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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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 |
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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 |
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