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A Novel Nonsense GLI3 Variant Is Associated With Polydactyly and Syndactyly in a Family by Blocking the Sonic Hedgehog Signaling Pathway
Polydactyly and syndactyly are congenital limb malformations that may occur either as non-syndromic or syndromic forms. In the present study, massively parallel sequencing was performed on a proband in a four-generation family with polydactyly and syndactyly to identify disease-causing variant(s). A...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693554/ https://www.ncbi.nlm.nih.gov/pubmed/33304378 http://dx.doi.org/10.3389/fgene.2020.542004 |
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author | Xiang, Ying Li, Xiaoliang Zhan, Zhiyan Feng, Jue Cai, Haiqing Li, Yanxin Fu, Qihua Xu, Yunlan Jiang, Hong Zhang, Xiaoqing |
author_facet | Xiang, Ying Li, Xiaoliang Zhan, Zhiyan Feng, Jue Cai, Haiqing Li, Yanxin Fu, Qihua Xu, Yunlan Jiang, Hong Zhang, Xiaoqing |
author_sort | Xiang, Ying |
collection | PubMed |
description | Polydactyly and syndactyly are congenital limb malformations that may occur either as non-syndromic or syndromic forms. In the present study, massively parallel sequencing was performed on a proband in a four-generation family with polydactyly and syndactyly to identify disease-causing variant(s). A pathogenic variant c.739C > T (p.Gln247(∗)) in the glioma-associated oncogene family zinc finger 3 (GLI3) gene was identified and co-segregated with the affected members of the family. Firstly, we examined GLI3 mRNA and GLI3 protein levels in peripheral blood mononuclear cells (PBMCs) of patients carrying this variant. The results showed that the truncated GLI3 p.Gln247(∗) (c.739C > T) protein was detectable in patients and the GLI3 transcript and protein levels were not significantly altered in the PBMCs of patients compared with healthy controls. Furthermore, functional analysis showed that the truncated GLI3 p.Gln247(∗) (c.739C > T) protein variant could lead to cytoplasmic accumulation of mutant protein and loss of ability to bind to the Suppressor of Fused protein. Alterations in protein expression levels of core components of the Sonic hedgehog signaling pathway were also observed. Our study shows that this novel GLI3 variant contributes to the malformations in this family and provides evidence for the mechanism by which GLI3 c.739C > T (p.Gln247(∗)) was implicated in the pathogenesis of polydactyly and syndactyly. |
format | Online Article Text |
id | pubmed-7693554 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-76935542020-12-09 A Novel Nonsense GLI3 Variant Is Associated With Polydactyly and Syndactyly in a Family by Blocking the Sonic Hedgehog Signaling Pathway Xiang, Ying Li, Xiaoliang Zhan, Zhiyan Feng, Jue Cai, Haiqing Li, Yanxin Fu, Qihua Xu, Yunlan Jiang, Hong Zhang, Xiaoqing Front Genet Genetics Polydactyly and syndactyly are congenital limb malformations that may occur either as non-syndromic or syndromic forms. In the present study, massively parallel sequencing was performed on a proband in a four-generation family with polydactyly and syndactyly to identify disease-causing variant(s). A pathogenic variant c.739C > T (p.Gln247(∗)) in the glioma-associated oncogene family zinc finger 3 (GLI3) gene was identified and co-segregated with the affected members of the family. Firstly, we examined GLI3 mRNA and GLI3 protein levels in peripheral blood mononuclear cells (PBMCs) of patients carrying this variant. The results showed that the truncated GLI3 p.Gln247(∗) (c.739C > T) protein was detectable in patients and the GLI3 transcript and protein levels were not significantly altered in the PBMCs of patients compared with healthy controls. Furthermore, functional analysis showed that the truncated GLI3 p.Gln247(∗) (c.739C > T) protein variant could lead to cytoplasmic accumulation of mutant protein and loss of ability to bind to the Suppressor of Fused protein. Alterations in protein expression levels of core components of the Sonic hedgehog signaling pathway were also observed. Our study shows that this novel GLI3 variant contributes to the malformations in this family and provides evidence for the mechanism by which GLI3 c.739C > T (p.Gln247(∗)) was implicated in the pathogenesis of polydactyly and syndactyly. Frontiers Media S.A. 2020-11-10 /pmc/articles/PMC7693554/ /pubmed/33304378 http://dx.doi.org/10.3389/fgene.2020.542004 Text en Copyright © 2020 Xiang, Li, Zhan, Feng, Cai, Li, Fu, Xu, Jiang and Zhang. 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 | Genetics Xiang, Ying Li, Xiaoliang Zhan, Zhiyan Feng, Jue Cai, Haiqing Li, Yanxin Fu, Qihua Xu, Yunlan Jiang, Hong Zhang, Xiaoqing A Novel Nonsense GLI3 Variant Is Associated With Polydactyly and Syndactyly in a Family by Blocking the Sonic Hedgehog Signaling Pathway |
title | A Novel Nonsense GLI3 Variant Is Associated With Polydactyly and Syndactyly in a Family by Blocking the Sonic Hedgehog Signaling Pathway |
title_full | A Novel Nonsense GLI3 Variant Is Associated With Polydactyly and Syndactyly in a Family by Blocking the Sonic Hedgehog Signaling Pathway |
title_fullStr | A Novel Nonsense GLI3 Variant Is Associated With Polydactyly and Syndactyly in a Family by Blocking the Sonic Hedgehog Signaling Pathway |
title_full_unstemmed | A Novel Nonsense GLI3 Variant Is Associated With Polydactyly and Syndactyly in a Family by Blocking the Sonic Hedgehog Signaling Pathway |
title_short | A Novel Nonsense GLI3 Variant Is Associated With Polydactyly and Syndactyly in a Family by Blocking the Sonic Hedgehog Signaling Pathway |
title_sort | novel nonsense gli3 variant is associated with polydactyly and syndactyly in a family by blocking the sonic hedgehog signaling pathway |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693554/ https://www.ncbi.nlm.nih.gov/pubmed/33304378 http://dx.doi.org/10.3389/fgene.2020.542004 |
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