Porcine IGF1 synonymous mutation alter gene expression and protein binding affinity with IGF1R

Cheng, Yi; Liu, Songcai; Gang, Wang; Wei, Wen‐Cheng J.; Huang, Shan; Yang, Rui; Geng, Hao; Li, Haoyang; Song, Jié; Sun, Lidan; Yu, Hao; Hao, Linlin

doi:10.1016/j.ijbiomac.2018.05.022

Cited by 17 publications

(21 citation statements)

References 34 publications

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“…In this study, we found that the difference in binding affinity with IGF-1 caused by the four Igf1r synonymous mutations. Another study showed that a synonymous mutation of its ligand IGF-1 has similar effects (Cheng et al, 2018), suggesting that these findings are not isolated cases. Meanwhile, the codon preference differences between the large and miniature pigs we observed suggested that codon usage may be a factor regulating body size.…”

Section: Discussionmentioning

confidence: 98%

“…Meanwhile, there is a strong heterogeneity between different haplotypes caused by synonymous mutations. For example, in the synonymous mutations found by Cheng et al (2018) the group with high mRNA stability and protein stability may have a low expression level. But Capon et al (2004) described that synonymous mutations with high mRNA stability showed high protein expression.…”

Section: Discussionmentioning

confidence: 99%

“…Mice with targeted IGF-1R overexpression in osteoblasts exhibit an increased bone formation rate and an enhanced trabecular and cortical bone volume ( Zhao et al, 2000 ). Numerous studies demonstrated that synonymous mutations have considerable biological effects on various processes, such as gene expression, gene stability, and protein conformation ( Fung et al, 2014 ; Chaney and Clark, 2015 ; Cheng et al, 2018 ). As a ligand-dependent receptor, stability and conformational changes in IGF-1R regulate IGF-1R activity and lead to differences in downstream functions.…”

Section: Discussionmentioning

confidence: 99%

“…Synonymous mutations can affect gene expressions by affecting gene stability and translation folding (Hunt et al, 2014;Cheng et al, 2018). We speculated that the haplotypes of Igf1r may be influenced by differences in mRNA and protein stability.…”

Section: Effects Of the Two Haplotypes Of Igf1r On Mrna And Protein Smentioning

confidence: 99%

“…With the development and utilization of miniature pig models, current studies focus on xenotransplantation and model construction. However, a systematic study on the formation mechanism of miniature pig dwarfism is lacking (Cheng et al, 2018;Cao et al, 2019). The genetic background of miniature pigs and the mechanism of dwarfism are the prerequisites of scientific research using miniature pig models.…”

Section: Introductionmentioning

confidence: 99%

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Synonymous Mutations of Porcine Igf1r Extracellular Domain Affect Differentiation and Mineralization in MC3T3-E1 Cells

Wang

Liu

et al. 2020

Front. Cell Dev. Biol.

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Owing to the wide application of miniature pigs in biomedicine, the formation mechanism of its short stature must be elucidated. The insulin-like growth factor 1 receptor (IGF-1R), which receives signals through the extracellular domain (ECD) binding with ligands, is crucial in regulating cell growth and bone matrix mineralization. In this study, two haplotypes of Igf1r with four synonymous mutations in the coding sequences of IGF-1R ECD between large pigs (LP) and Bama pigs (BM) were stably expressed in the Igf1r-knockout MC3T3-E1 cells and named as MC3T3-LP cells (LP group) and MC3T3-BM cells (BM group), respectively. IGF-1R expression was lower in the BM group than in the LP group both in terms of transcription and translation levels, and IGF-1R expression inhibited cell proliferation. In addition, IGF-1R expression in the BM group promoted early-stage differentiation but delayed late-stage differentiation, which not only suppressed the expression of bone-related factors but also reduced alkaline phosphatase activity and calcium deposition. Moreover, different haplotypes of Igf1r changed the stability and conformation of the protein, further affecting the binding with IGF-1. Our data indicated that the four synonymous mutations of IGF1R ECD encoded by affect gene transcription and translation, thereby further leading to differences in the downstream pathways and functional changes of osteoblasts.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of the Two Haplotypes Of Igf1r On Mrna And Protein Smentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synonymous Mutations of Porcine Igf1r Extracellular Domain Affect Differentiation and Mineralization in MC3T3-E1 Cells

Wang

Liu

et al. 2020

Front. Cell Dev. Biol.

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Effects of 14 F9 synonymous codon variants on hemophilia B expression: Alteration of splicing along with protein expression

Zhang

Chen

et al. 2022

Human Mutation

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There is growing evidence that synonymous codon variants (SCVs) can cause disease through the disruption of different processes of protein production. The aim of the study is to investigate whether the 14 SCVs reported in the F9 variant database were the pathogenic causes of hemophilia B. The impacts of SCVs on splicing and protein expression were detected using a combination of in silico prediction, in vitro minigene splicing assay and cell expression detection. The splicing transcripts were identified and quantified by co-amplification fluorescent PCR. The mechanism of splicing was verified by a modified pU1snRNA and pU7snRNA approach. Aberrant splicing patterns were found in eight SCVs. Five of the 8 SCVs produced almost all aberrant splicing isoforms, which were expected to truncate protein, three of them presented a partial defect on both splicing and protein secretion, the overall effects were consistent with the residual Factor IX activity of the affected cases. Neither the pre-messenger RNA (mRNA) splicing process nor the protein function was impaired in the rest six SCVs. In conclusion, our study firstly revealed the pathogenic mechanism of the 14 F9 SCVs and highlighted the importance of performing mRNA splicing analysis and protein expression studies of SCVs in inherited disorders.

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A miR-511-binding site SNP in the 3′UTR of IGF-1 gene is associated with proliferation and apoptosis of PK-15 cells

Wei

Wang

Cheng

et al. 2019

In Vitro Cell.Dev.Biol.-Animal

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Porcine IGF1 synonymous mutation alter gene expression and protein binding affinity with IGF1R

Cited by 17 publications

References 34 publications

Synonymous Mutations of Porcine Igf1r Extracellular Domain Affect Differentiation and Mineralization in MC3T3-E1 Cells

Synonymous Mutations of Porcine Igf1r Extracellular Domain Affect Differentiation and Mineralization in MC3T3-E1 Cells

Effects of 14 F9 synonymous codon variants on hemophilia B expression: Alteration of splicing along with protein expression

A miR-511-binding site SNP in the 3′UTR of IGF-1 gene is associated with proliferation and apoptosis of PK-15 cells

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