Mutations in fibroblast growth factor (FGF8) and FGF10 identified in patients with conotruncal defects
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Journal of Translational Medicine Open Access
RESEARCH
Mutations in fibroblast growth factor (FGF8) and FGF10 identified in patients with conotruncal defects Kun Sun* , Shuang Zhou, Qingjie Wang, Zhuo Meng, Jiayu Peng, Yue Zhou, Wenting Song, Jian Wang* and Sun Chen*
Abstract Background: Conotruncal defects (CTDs) are a type of heterogeneous congenital heart diseases (CHDs), but little is known about their etiology. Increasing evidence has demonstrated that fibroblast growth factor (FGF) 8 and FGF10 may be involved in the pathogenesis of CTDs. Methods: The variants of FGF8 and FGF10 in unrelated Chinese Han patients with CHDs (n = 585), and healthy controls (n = 319) were investigated. The expression and function of these patient-identified variants were detected to confirm the potential pathogenicity of the non-synonymous variants. The expression of FGF8 and FGF10 during the differentiation of human embryonic stem cells (hESCs) to cardiomyocytes and in Carnegie stage 13 human embryo was also identified. Results: Two probable deleterious variants (p.C10Y, p.R184H) of FGF8 and one deletion mutant (p.23_24del) of FGF10 were identified in three patients with CTD. Immunofluorescence suggested that variants did not affect the intracellular localization, whereas ELISA showed that the p.C10Y and p.23_24del variants reduced the amount of secreted FGF8 and FGF10, respectively. Quantitative RT-PCR and western blotting showed that the expression of FGF8 and FGF10 variants was increased compared with wild-type; however, their functions were reduced. And we found that FGF8 and FGF10 were expressed in the outflow tract (OFT) during human embryonic development, and were dynamically expressed during the differentiation of hESCs into cardiomyocytes. Conclusion: Our results provided evidence that damaging variants of FGF8 and FGF10 were likely contribute to the etiology of CTD. This discovery expanded the spectrum of FGF mutations and underscored the pathogenic correlation between FGF mutations and CTD. Keywords: Conotruncal defect, Fibroblast growth factor 8, Fibroblast growth factor 10, Target sequencing Background Conotruncal defects (CTDs) are a complex type of congenital heart diseases (CHDs) with an approximate prevalence of 0.1‰ among live births [1], and approximately *Correspondence: [email protected]; [email protected]. cn; [email protected] Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, No. 1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
25–30% of all non-syndromic CHDs. CTDs include the following conditions: tetralogy of Fallot (TOF), double outlet of right ventricle (DORV), pulmonary atresia with ventricular septal defect (PA/VSD), transposition of the great arteries (TGA), interrupted aortic arch (IAA), and persistent truncus arteriosus (PTA). CTDs are the most common type of cyanotic CHDs [2]. They usually require catheter-based or surgical treatment early in life, but the mortality rate remains high [3]. The outflow trac
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