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Novel FGFR1 Variants Are Associated with Congenital Scoliosis

FGFR1 encodes a transmembrane cytokine receptor, which is involved in the early development of the human embryo and plays an important role in gastrulation, organ specification and patterning of various tissues. Pathogenic FGFR1 variants have been associated with Kallmann syndrome and hypogonadotrop...

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Autores principales: Wang, Shengru, Chai, Xiran, Yan, Zihui, Zhao, Sen, Yang, Yang, Li, Xiaoxin, Niu, Yuchen, Lin, Guanfeng, Su, Zhe, Wu, Zhihong, Zhang, Terry Jianguo, Wu, Nan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393897/
https://www.ncbi.nlm.nih.gov/pubmed/34440300
http://dx.doi.org/10.3390/genes12081126
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author Wang, Shengru
Chai, Xiran
Yan, Zihui
Zhao, Sen
Yang, Yang
Li, Xiaoxin
Niu, Yuchen
Lin, Guanfeng
Su, Zhe
Wu, Zhihong
Zhang, Terry Jianguo
Wu, Nan
author_facet Wang, Shengru
Chai, Xiran
Yan, Zihui
Zhao, Sen
Yang, Yang
Li, Xiaoxin
Niu, Yuchen
Lin, Guanfeng
Su, Zhe
Wu, Zhihong
Zhang, Terry Jianguo
Wu, Nan
author_sort Wang, Shengru
collection PubMed
description FGFR1 encodes a transmembrane cytokine receptor, which is involved in the early development of the human embryo and plays an important role in gastrulation, organ specification and patterning of various tissues. Pathogenic FGFR1 variants have been associated with Kallmann syndrome and hypogonadotropic hypogonadism. In our congenital scoliosis (CS) patient series of 424 sporadic CS patients under the framework of the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study, we identified four unrelated patients harboring FGFR1 variants, including one frameshift and three missense variants. These variants were predicted to be deleterious by in silico prediction and conservation analysis. Signaling activities and expression levels of the mutated protein were evaluated in vitro and compared to that of the wild type (WT) FGFR1. As a result, the overall protein expressions of c.2334dupC, c.2339T>C and c.1261A>G were reduced to 43.9%, 63.4% and 77.4%, respectively. By the reporter gene assay, we observed significantly reduced activity for c.2334dupC, c.2339T>C and c.1261A>G, indicating the diminished FGFR1 signaling pathway. In conclusion, FGFR1 variants identified in our patients led to only mild disruption to protein function, caused milder skeletal and cardiac phenotypes than those reported previously.
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spelling pubmed-83938972021-08-28 Novel FGFR1 Variants Are Associated with Congenital Scoliosis Wang, Shengru Chai, Xiran Yan, Zihui Zhao, Sen Yang, Yang Li, Xiaoxin Niu, Yuchen Lin, Guanfeng Su, Zhe Wu, Zhihong Zhang, Terry Jianguo Wu, Nan Genes (Basel) Article FGFR1 encodes a transmembrane cytokine receptor, which is involved in the early development of the human embryo and plays an important role in gastrulation, organ specification and patterning of various tissues. Pathogenic FGFR1 variants have been associated with Kallmann syndrome and hypogonadotropic hypogonadism. In our congenital scoliosis (CS) patient series of 424 sporadic CS patients under the framework of the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study, we identified four unrelated patients harboring FGFR1 variants, including one frameshift and three missense variants. These variants were predicted to be deleterious by in silico prediction and conservation analysis. Signaling activities and expression levels of the mutated protein were evaluated in vitro and compared to that of the wild type (WT) FGFR1. As a result, the overall protein expressions of c.2334dupC, c.2339T>C and c.1261A>G were reduced to 43.9%, 63.4% and 77.4%, respectively. By the reporter gene assay, we observed significantly reduced activity for c.2334dupC, c.2339T>C and c.1261A>G, indicating the diminished FGFR1 signaling pathway. In conclusion, FGFR1 variants identified in our patients led to only mild disruption to protein function, caused milder skeletal and cardiac phenotypes than those reported previously. MDPI 2021-07-24 /pmc/articles/PMC8393897/ /pubmed/34440300 http://dx.doi.org/10.3390/genes12081126 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Shengru
Chai, Xiran
Yan, Zihui
Zhao, Sen
Yang, Yang
Li, Xiaoxin
Niu, Yuchen
Lin, Guanfeng
Su, Zhe
Wu, Zhihong
Zhang, Terry Jianguo
Wu, Nan
Novel FGFR1 Variants Are Associated with Congenital Scoliosis
title Novel FGFR1 Variants Are Associated with Congenital Scoliosis
title_full Novel FGFR1 Variants Are Associated with Congenital Scoliosis
title_fullStr Novel FGFR1 Variants Are Associated with Congenital Scoliosis
title_full_unstemmed Novel FGFR1 Variants Are Associated with Congenital Scoliosis
title_short Novel FGFR1 Variants Are Associated with Congenital Scoliosis
title_sort novel fgfr1 variants are associated with congenital scoliosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393897/
https://www.ncbi.nlm.nih.gov/pubmed/34440300
http://dx.doi.org/10.3390/genes12081126
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