目的应用Affymetrix SNP 6.0芯片技术筛选先天性小耳畸形的候选致病基因。方法对3例小耳畸形患者血液基因组进行Affymetrix SNP 6.0芯片分析,采用Birdseed软件分析样本的芯片数据,通过Minor Allele Frequency对在患者和汉族人参考样本...目的应用Affymetrix SNP 6.0芯片技术筛选先天性小耳畸形的候选致病基因。方法对3例小耳畸形患者血液基因组进行Affymetrix SNP 6.0芯片分析,采用Birdseed软件分析样本的芯片数据,通过Minor Allele Frequency对在患者和汉族人参考样本中有显著差异的单核苷酸多态性(SNP)进行筛选。结果得到SNP相关基因4 180个,根据已知文献收集和耳部发育相关并被SNP 6.0注释的基因共5个,包括MSX1,MSX2,GSC,HOXA2和PRKRA。结论应用Affymetrix SNP 6.0芯片技术筛选出5个先天性小耳畸形的候选致病基因,分别是MSX1,MSX2,GSC,HOXA2和PRKRA。展开更多
The goal of this study was to identify MSX1 gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants.Whole-exome sequencing(WES)and Sanger sequenc...The goal of this study was to identify MSX1 gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants.Whole-exome sequencing(WES)and Sanger sequencing were performed to identify the causal gene variants in five families with nonsyndromic oligodontia,and a series of bioinformatics databases were used for variant confirmation and functional prediction.Phenotypic characterization of the members of these families was described,and an in vitro analysis was performed for functional evaluation.Five novel MSX1 heterozygous variants were identified:three missense variants[c.662A>C(p.Q221P),c.670C>T(p.R224C),and c.809C>T(p.S270L)],one nonsense variant[c.364G>T(p.G122*)],and one frameshift variant[c.277delG(p.A93Rfs*67)].Preliminary in vitro studies demonstrated that the subcellular localization of MSX1 was abnormal with the p.Q221P,p.R224C,p.G122*,and p.A93Rfs*67 variants compared to the wild type.Three variants(p.Q221P,p.G122*,and p.A93Rfs*67)were classified as pathogenic or likely pathogenic,while p.S270L and p.R224C were of uncertain significance in the current data.Moreover,we summarized and analysed the MSX1-related tooth agenesis positions and found that the type and variant locus were not related to the severity of tooth loss.Our results expand the variant spectrum of nonsyndromic oligodontia and provide valuable information for genetic counselling.展开更多
目的研究同源异型盒基因1(muscle segment homeobox1,MSX1)A274V多态性与非综合征性唇腭裂(non-syndromic cleft lip with or without cleft palate,NSCL/P)的关系。方法利用聚合酶链反应-限制性片段长度多态性方法,在162例非综合性唇...目的研究同源异型盒基因1(muscle segment homeobox1,MSX1)A274V多态性与非综合征性唇腭裂(non-syndromic cleft lip with or without cleft palate,NSCL/P)的关系。方法利用聚合酶链反应-限制性片段长度多态性方法,在162例非综合性唇腭裂患者和195例正常对照中,对MSX1基因A274V单核苷酸多态性进行检测。分析基因型发布频率是否符合Hardy-Weinberg平衡定律。应用UNPHASED软件包分析多态性位点与非综合性唇腭裂的相关性。结果 MSX1 A274V多态性基因型频率分布符合Hardy-Weinberg平衡定律。MSX1 A274V等位基因分布在NSCL/P组与对照组之间有显著性差异(P<0.05)。在NSCL/P组中T等位基因的频率明显高于对照组。结论 MSX1 A274V多态性位点与中国人群非综合性唇腭裂形成相关联。展开更多
The msh homeobox 1(Msx1)and msh homeobox 2(Msx2)coordinate in myoblast differentiation and also contribute to muscle defects if altered during development.Deciphering the downstream signaling networks of Msx1 and Msx2...The msh homeobox 1(Msx1)and msh homeobox 2(Msx2)coordinate in myoblast differentiation and also contribute to muscle defects if altered during development.Deciphering the downstream signaling networks of Msx1 and Msx2 in myoblast differentiation will help us to understand the molecular events that contribute to muscle defects.Here,the proteomics characteristics in Msx1-and Msx2-mediated myoblast differentiation was evaluated using isobaric tags for the relative and absolute quantification labeling technique(iTRAQ).The downstream regulatory proteins of Msx1-and Msx2-mediated differentiation were identified.Bioinformatics analysis revealed that these proteins were primarily associated with xenobiotic metabolism by cytochrome P450,fatty acid degradation,glycolysis/gluconeogenesis,arginine and proline metabolism,and apoptosis.In addition,our data show Acta1 was probably a core of the downstream regulatory networks of Msx1 and Msx2 in myoblast differentiation.展开更多
Development of the secondary palate displays molecular heterogeneity along the anterior-posterior axis;however, the underlying molecular mechanism remains largely unknown. MSX1 is an anteriorly expressed transcription...Development of the secondary palate displays molecular heterogeneity along the anterior-posterior axis;however, the underlying molecular mechanism remains largely unknown. MSX1 is an anteriorly expressed transcription repressor required for palate development. Here, we investigate the role of Msx1 in regional patterning of the secondary palate. The Wnt1-Cre-mediated expression of Msx1(Rosa Msx1^(Wnt1-Cre))throughout the palatal mesenchyme leads to cleft palate in mice, associated with aberrant cell proliferation and cell death. Osteogenic patterning of the hard palate in Rosa Msx1^(Wnt1-Cre)mice is severely impaired, as revealed by a marked reduction in palatine bone formation and decreased expression of the osteogenic regulator Sp7. Overexpression and knockout of Msx1 in mice show that the transcription repressor promotes the expression of the anterior palate-specific Alx1 but represses the expression of the medialposterior palate genes Barx1, Meox2, and Tbx22. Furthermore, Tbx22 constitutes a direct Msx1 target gene in the secondary palate, suggesting that Msx1 can directly repress the expression of medial-posterior specific genes. Finally, we determine that Sp7 is downstream of Tbx22 in palatal mesenchymal cells,suggesting that a Msx1/Tbx22/Sp7 axis participates in the regulation of palate development. Our findings unveil a novel role for Msx1 in regulating the anterior-posterior growth and patterning of the secondary palate.展开更多
文摘目的应用Affymetrix SNP 6.0芯片技术筛选先天性小耳畸形的候选致病基因。方法对3例小耳畸形患者血液基因组进行Affymetrix SNP 6.0芯片分析,采用Birdseed软件分析样本的芯片数据,通过Minor Allele Frequency对在患者和汉族人参考样本中有显著差异的单核苷酸多态性(SNP)进行筛选。结果得到SNP相关基因4 180个,根据已知文献收集和耳部发育相关并被SNP 6.0注释的基因共5个,包括MSX1,MSX2,GSC,HOXA2和PRKRA。结论应用Affymetrix SNP 6.0芯片技术筛选出5个先天性小耳畸形的候选致病基因,分别是MSX1,MSX2,GSC,HOXA2和PRKRA。
基金supported by the National Natural Science Foundation of China(81970902,81771054,and 81600846).
文摘The goal of this study was to identify MSX1 gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants.Whole-exome sequencing(WES)and Sanger sequencing were performed to identify the causal gene variants in five families with nonsyndromic oligodontia,and a series of bioinformatics databases were used for variant confirmation and functional prediction.Phenotypic characterization of the members of these families was described,and an in vitro analysis was performed for functional evaluation.Five novel MSX1 heterozygous variants were identified:three missense variants[c.662A>C(p.Q221P),c.670C>T(p.R224C),and c.809C>T(p.S270L)],one nonsense variant[c.364G>T(p.G122*)],and one frameshift variant[c.277delG(p.A93Rfs*67)].Preliminary in vitro studies demonstrated that the subcellular localization of MSX1 was abnormal with the p.Q221P,p.R224C,p.G122*,and p.A93Rfs*67 variants compared to the wild type.Three variants(p.Q221P,p.G122*,and p.A93Rfs*67)were classified as pathogenic or likely pathogenic,while p.S270L and p.R224C were of uncertain significance in the current data.Moreover,we summarized and analysed the MSX1-related tooth agenesis positions and found that the type and variant locus were not related to the severity of tooth loss.Our results expand the variant spectrum of nonsyndromic oligodontia and provide valuable information for genetic counselling.
文摘目的研究同源异型盒基因1(muscle segment homeobox1,MSX1)A274V多态性与非综合征性唇腭裂(non-syndromic cleft lip with or without cleft palate,NSCL/P)的关系。方法利用聚合酶链反应-限制性片段长度多态性方法,在162例非综合性唇腭裂患者和195例正常对照中,对MSX1基因A274V单核苷酸多态性进行检测。分析基因型发布频率是否符合Hardy-Weinberg平衡定律。应用UNPHASED软件包分析多态性位点与非综合性唇腭裂的相关性。结果 MSX1 A274V多态性基因型频率分布符合Hardy-Weinberg平衡定律。MSX1 A274V等位基因分布在NSCL/P组与对照组之间有显著性差异(P<0.05)。在NSCL/P组中T等位基因的频率明显高于对照组。结论 MSX1 A274V多态性位点与中国人群非综合性唇腭裂形成相关联。
基金This work was supported by the grant from the National Natural Science Foundation Grant of China to Jingqiang Wang(31972885).
文摘The msh homeobox 1(Msx1)and msh homeobox 2(Msx2)coordinate in myoblast differentiation and also contribute to muscle defects if altered during development.Deciphering the downstream signaling networks of Msx1 and Msx2 in myoblast differentiation will help us to understand the molecular events that contribute to muscle defects.Here,the proteomics characteristics in Msx1-and Msx2-mediated myoblast differentiation was evaluated using isobaric tags for the relative and absolute quantification labeling technique(iTRAQ).The downstream regulatory proteins of Msx1-and Msx2-mediated differentiation were identified.Bioinformatics analysis revealed that these proteins were primarily associated with xenobiotic metabolism by cytochrome P450,fatty acid degradation,glycolysis/gluconeogenesis,arginine and proline metabolism,and apoptosis.In addition,our data show Acta1 was probably a core of the downstream regulatory networks of Msx1 and Msx2 in myoblast differentiation.
基金supported by grants from the National Natural Scientific Foundation of China (81771028 and 317771593)Medical Health Science and Technology Project of Zhejiang (2021KY891)Medical Health Science and Technology Major Project of Hangzhou (Z20200046)。
文摘Development of the secondary palate displays molecular heterogeneity along the anterior-posterior axis;however, the underlying molecular mechanism remains largely unknown. MSX1 is an anteriorly expressed transcription repressor required for palate development. Here, we investigate the role of Msx1 in regional patterning of the secondary palate. The Wnt1-Cre-mediated expression of Msx1(Rosa Msx1^(Wnt1-Cre))throughout the palatal mesenchyme leads to cleft palate in mice, associated with aberrant cell proliferation and cell death. Osteogenic patterning of the hard palate in Rosa Msx1^(Wnt1-Cre)mice is severely impaired, as revealed by a marked reduction in palatine bone formation and decreased expression of the osteogenic regulator Sp7. Overexpression and knockout of Msx1 in mice show that the transcription repressor promotes the expression of the anterior palate-specific Alx1 but represses the expression of the medialposterior palate genes Barx1, Meox2, and Tbx22. Furthermore, Tbx22 constitutes a direct Msx1 target gene in the secondary palate, suggesting that Msx1 can directly repress the expression of medial-posterior specific genes. Finally, we determine that Sp7 is downstream of Tbx22 in palatal mesenchymal cells,suggesting that a Msx1/Tbx22/Sp7 axis participates in the regulation of palate development. Our findings unveil a novel role for Msx1 in regulating the anterior-posterior growth and patterning of the secondary palate.
