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Mutations in fibroblast growth factor (FGF8) and FGF10 identified in patients with conotruncal defects.

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.

SUBMITTER: Zhou S

PROVIDER: S-EPMC7362408 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveColorectal cancer (CRC) imposes great health burdens worldwide. Growth factors contribute to cell growth, differentiation, angiogenesis and, most importantly, tumour formation in many types of cancers. Natural antisense transcripts (NATs) are inclusively predicted to play a major role in cancer progression. The present study aims to evaluate the relationship of fibroblast growth factor 10 (FGF10) and novel long noncoding RNA (lncRNA) antisense FGF10 (FGF10AS) expression with clinicopathologic features in CRC progression to designate a biomarker for CRC early detection.Materials and methodsThis cross-sectional study was conducted on 100 CRC tumour and parallel adjacent normal tissues. We added 30 normal cases to enhance accuracy of the test. The expression levels of FGF10 and FGF10AS were evaluated by real-time polymerase chain reaction (PCR). The findings were validated by measuring expression levels in the HT29 and SW480 cell lines. Immunohistochemistry analysis was performed systematically to evaluate FGF10 protein expression. The Mann-Whitney U test with Cox regression analysis were applied. P<0.05 were designated as significant.ResultsA significant increase in expression was observed in FGF10 (P<0.001) along with a significant decrease in FGF10AS (P<0.02) in the tumour tissues in comparison with the adjacent normal tissues. Upregulation of FGF10 and downregulation of FGF10AS expression were strongly correlated with the Tumour, Node, Metastasis (TNM) stage (P<0.007 and P<0.004), vascular invasion (P<0.03 and P<0.01), lymph invasion (P<0.02 and P<0.04), and differentiation (P<0.01 and P<0.02), respectively. Moreover, the area under the receiver operating characteristic (ROC) curve for the prognostic value of FGF10 was about 0.84 (95% confidence interval [CI]: 0.771-0.912). Linear regression analysis confirmed a negative correlation between FGF10 expression and its antisense transcript (r=-0.02).ConclusionThe relationship between the expression levels of FGF10 and FGF10AS in tumour tissues and adjacent normal tissues indicated that sense and antisense FGF RNAs could be remarkable prognostic biomarkers for achieving effective and primitive treatment.

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Mutations in fibroblast growth factor (FGF8) and FGF10 identified in patients with conotruncal defects.

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