FOXC2基因在先天发育缺陷中的变异分析
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摘要
FOXC2基因在先天发育缺陷中的变异分析
在胚胎发育过程中,受到环境、遗传等多种因素的影响,胎儿在形态、组织结构及生理功能上的发育受到影响,常发生胎儿流产、死胎或存在出生缺陷,给家庭、社会带来沉重的经济与心理负担。先天性发育缺陷是流产、死胎、死产和新生儿死亡的主要原因之一。我国近年出生缺陷发生率大约波动在11‰～18‰,是严重影响出生人口健康素质的因素。寻找先天性发育缺陷的确切病因,进一步揭示其发病机理,对于开展产前预防、诊断及干预,提高出生人口素质具有重要的意义。
人叉头框-C2基因是具有DNA-结合域的翼状螺旋转录因子家族中的一员,在进化上具有高度保守性。定位于16q22- 16q24,只包含一个单独编码的外显子,没有内含子,cDNA全长为1506bp。其编码的蛋白质共有494个氨基酸残基。已有动物实验证明,Foxc2基因在胚胎发育过程中有着重要的作用,敲除Foxc2基因的小鼠可在心血管、软骨组织、肾脏、主动脉弓及眼睛间质等多部位表现出发育异常。人的FOXC2已经被克隆出来,人类的FOXC2基因和小鼠Foxc2基因有95%以上的同源性。人类FOXC2基因与临床的关联性最早是在家族遗传性疾病淋巴水肿-双睫毛综合征中被确认,LD综合征是一种罕见的常染色体显性遗传病。临床特征是下肢水肿和双重睫毛,还有个体合并静脉曲张、先天性心脏病和上睑下垂等,对LD家族的遗传分析发现FOXC2基因的突变和LD综合征发病密切相关。在动物实验中发现Foxc2与淋巴管的发生、中轴骨骼的发育、心血管系统及泌尿系统的发育有关,然而,在人类胚胎发育过程中,该基因的分子生物学表现及功能状况尚不清楚,故对FOXC2在胚胎发生中的作用及与先天发育缺陷的关系等方面进行研究。
第1部分先天发育缺陷胎儿的类型分析
目的:分析了长春地区先天性发育缺陷的类型,为重点缺陷的预防提供理论依据。方法:收集长春市多家医院妇产科就诊的流产或引产死胎,伴发育缺陷胎儿73例。对明显的发育畸形进行记录。分析异常器官。结果:在73例先天性发育异常胎儿中,男性41例,女性32例。由于在一个胎儿可以发生多组织器官的畸形或缺陷,共发现了93个器官或组织发育畸形,致宫内死胎共32例。神经管异常47例,占全部发育异常胎儿的64.3%(47/73),占发育畸形的构成比例为50.5%(47/93)。心血管发育异常病例19例,占全部发育异常胎儿的26%(19/73);心血管发育异常死胎15例,心血管发育异常儿胎死宫内发生率为78.9%(15/19),占畸形胎儿死胎总数的46.9%(15/32)。结论:在73例先天性发育缺陷胎儿中,男性比例高于女性。神经管发育缺陷是长春地区最主要的先天发育缺陷。心血管发育异常是胎死宫内最主要原因,也是本地区主要的先天发育缺陷。发现与成人LD综合征相似的淋巴水肿胎儿。
第2部分FOXC2是人胚胎多器官发育重要的转录因子
目的:研究FOXC2是否参与人胚胎发生发育过程。方法:通过免疫组化方法分析了FOXC2在人胚胎发育过程中的作用。结果:FOXC2在人胚胎最早期的头部间充质发生发育过程中起作用。在肋骨软骨的生发中心肋软骨始基细胞核看到FOXC2蛋白强表达。心脏的大血管、主动脉全层、心室内膜及心室壁外层可见到FOXC2的表达。胚胎肾脏的髓质可见到FOXC2的表达。结论:FOXC2基因是中轴骨骼的发育过程中必不可缺少的转录因子;FOXC2在人胚胎心血管系统发生、发育过程中发挥重要的生物功效;人胚胎期肾脏的发育也需要FOXC2参与。
第3部分胎儿先天发育缺陷危险因素及FOXC2基因多态性分析
目的:了解先天发育缺陷的危险因素及FOXC2基因的变异与先天发育缺陷发生的关系。方法:对73例先天发育缺陷胎儿的相关危险因素进行调查、登记和分析。提取发育缺陷胎儿基因组DNA,通过PCR反应扩增出包含FOXC2 cDNA的目的片段,送检测序,进行基因多态性分析。结果:父母亲的不良生活习惯、家族发育缺陷遗传史、父母特殊工作史、特殊化学试剂接触史、未行孕前检查及孕早期未补充叶酸、维生素等与胎儿先天性发育缺陷的发生密切相关。对68例发育缺陷胎儿成功测序样本进行分析,共存在20个突变位点,其中引起编码氨基酸改变的突变点共15个。此15个有效突变位点集中在12个病例(包括神经管发育异常、心血管发育异常、淋巴水肿及多囊肾胎儿)中,FOXC2基因突变发生率为17.6%(12/68)。结论:孕期多种因素可以导致先天发育缺陷的发生率增加。基因变异分析发现了胚胎发育期神经管、心血管发育异常、淋巴水肿及多囊肾等先天发育缺陷胎儿存在FOXC2基因多点变异;胚胎期淋巴水肿胎儿显示了与成人LD综合征相似的高FOXC2基因突变率;胚胎期发育缺陷胎儿FOXC2基因的有效突变导致编码氨基酸改变,证明FOXC2基因变化与胎儿先天缺陷的发生密切相关。
第4部分先天性心脏病危险因素及FOXC2基因多态性分析
目的:了解先心病的危险因素及FOXC2基因的变异与先心病发生的关系。方法:对34例先心病患者的相关危险因素进行调查、登记和分析。提取先心病患者基因组DNA,通过PCR反应扩增出包含FOXC2 cDNA的目的片段,送检测序,进行基因多态性分析。结果:父母亲的吸烟、饮酒等不良生活习惯、父母特殊化学试剂接触史、家族发育缺陷遗传史、孕早期服药、孕早期感冒等均与CHD的发生有关联。成功测序29例先心病患者中,引起编码氨基酸改变的突变位点有9个,集中在7例患者中,有效突变率为24.1%(7/29)。结论:孕期多种不良因素可以导致先心病发病率的增加。CHD患者的FOXC2基因突变引起了编码氨基酸的改变,表明FOXC2的基因突变与CHD的发生密切相关;先心病患者与心脏畸形胎儿共同存在FOXC2基因216bp、255bp和505bp位点的突变,证明这三个突变位点是先心病的突变热点。
Mutation analysis of FOXC2 gene in congenital developmental defect
In embryonic development, by environmental, genetic and other factors, the fetus development of the appearance, structure and physiological function were affected, fetal abortion, stillbirth or birth defects often exist,it's a heavy economic and psychological burden to the family and society. Congenital developmental defects were large proportion mortality in the fetal and neonatal. it's a serious impact on quality of health diathesis. Find the exact cause of congenital defects, and further reveal its pathogenesis, it's great significance for prenatal prevention, diagnosis and intervention, and improve the quality of births.
Human forkhead box c2 (FOXC2),a member of the winged helix transcription factors family with DNA-binding domains, was evolutionarily highly conserved.The positiong was 16q22-16q24, it only Contained a single coding exon, no intron, the length of cDNA was 1506bp. The protein encoded 494 amino acid residues. Animal experiments have proved, Foxc2 gene in embryonic development played an important role. in gene knockout mice showed abnormalities in cardiovascular, cartilage, kidney, aortic arch and the eyes and other parts of the stroma.Human FOXC2 have been cloned, the human FOXC2 gene and the gene in mice Foxc2 had more than 95% homology.The first relevance of the human FOXC2 gene and clinical disease was confirmed in a hereditary disease-lymphedema -distichiasis syndrome.LD syndrome was a rare autosomal dominant genetic disease. The clinical characteristics were lower limb edema and double eyelashes, and the individual merge varicose veins, congenital heart disease and ptosis.The genetic analysis of LD family found that the FOXC2 gene mutations and LD syndrome were closely related. In animal experiments,it has found that Foxc2 was related with lymphangiogenesis, the development of axial skeleton, cardiovascular system and urinary system.However, in human embryonic development, the gene expression of molecular biology and functional status is not clear, So we did the the research,we want to know the relationship with FOXC2's role in embryogenesis and congenital developmental defects.
PartⅠAutopsy type analysis of congenital developmental defects fetal
Objective: Analysis of congenital developmental defects in Changchun, and provide the theoretical basis on the prevention of point defects.Methods: Collected 73 cases of developmental defects fetus that were abortion and induced in Obstetrics and Gynecology department of several hospital in Changchun. We recorded obvious malformations and analysis of abnormal organs. Results: In the 73 cases of congenital abnormalities fetus, male were 41 cases, female were 32 cases. Since a fetus could occur malformations or defects in several tissues and organs, 93 cases of malformations were found in different organ and tissue,they caused 32 cases intrauterine fetal death. The largest number of malformations were neural tube defects, 47 cases. accounting for 64.3%(47/73)of fetal abnormalities,the composition ratio of total malformations was 50.5%(47/93).The number of cardiovascular abnormalities were 19, accounting for 26% (19/73)of fetal abnormalities,the composition ratio of total malformations was 20.4% (19/93). Stillbirth of cardiovascular abnormalities were 15 cases, cardiovascular abnormalities fetal death rate was 78.9% (15/19), accounting for the total number of abnormal stillbirth 46.9% (15/32).Conclusion: In 73 cases of congenital developmental defects fetus, the proportion of male was more than female. Neural tube defects was the most important congenital developmental defects in Changchun area. Cardiovascular abnormalities in this region was also the major congenital developmental defects,it was the main reason caused intrauterine fetal death.We found lymphedema fetus similar to adult LD syndrome.
PartⅡFOXC2's a important transcription factor in the human embryonic development of many organs
Objective: To know if FOXC2 was involved in the development of human embryos. Methods:We analyzed FOXC2's role in the human embryonic development by Immunohistochemical methods.Results: In the human embryo,FOXC2 first occurred in the head mesenchyme. Then In the costal rib cartilage primordial germinal center found strong expression of FOXC2 protein in the nucleus. We could found FOXC2 expression in the the great vessels of heart, whole layer of aortic,the ventricular endocardium and the ventricular outer wall. Embryonic kidney medulla also had FOXC2 expression. Conclusion: FOXC2 gene was the indispensable transcription factor in the process of development of central axial skeleton; FOXC2 played an important biological effect in the process of development of human embryonic cardiovascular system; The development of human embryonic kidney also need FOXC2 participation.
PartⅢThe analysis of risk factors for fetal congenital developmental defects and FOXC2 gene polymorphism
Objective: To understand the relationship of risk factors with congenital developmental defects ,and FOXC2 gene mutation with congenital developmental defects.Methods: The risk factors were investigated, registed and analysis of 73 cases congenital developmental defects fetus.Extract their genomic DNA, amplified FOXC2 cDNA fragment by PCR,and inspect sequencing,then analysis the genetic polymorphism. Results: The occurrence of congenital defects fetus were closely related with parents' bad habits, family heredity history of developmental defects,parents' special work history, history of exposure to specific chemical agents, no progestation examination and without supply folic acid and vitamins in early pregnancy. 68 cases of target DNA fragment were successful sequencing,there were 20 mutations, which caused 15 amino acid changes in sites. The 15 effected mutations concentrated in 12 cases (including the neural tube defects, cardiovascular abnormalities, fetal lymphedema and polycystic kidney fetus), FOXC2 gene mutation rate was 17.6% (12/68). Conclusion: Gene mutation analysis found FOXC2 multiple mutation spots in embryogenesis congenital defects with neural tube defects, cardiovascular dysplasia,lymphedema and polycystic kidney.The embryonic period lymphedema fetus showed similar high FOXC2 mutation rate to adult LD syndrome.The FOXC2 mutations of embryonic developmental defectfetus caused change of encoding amino acids,so FOXC2 gene mutations had close relationship.with birth defects.
PartⅣThe analysis of risk factors for congenital heart disease and FOXC2 gene polymorphism
Objects: To understand the relationship of risk factors with congenital heart disease,and FOXC2 gene mutation with congenital heart disease.Methods: Collected 34 children's myocardium with congenital heart disease in cardiac surgery of the First Hospital of Jilin University.The risk factors were investigated, registed and analysis of 34 cases CHD patients.Extract their genomic DNA, amplified FOXC2 cDNA fragment by PCR,and inspect sequencing,then analysis the genetic polymorphism. Results: The occurrence of CHD were closely related with parents' bad habits(smoking and drinking), history of exposure to specific chemical agents, family heredity history of developmental defects, drug administration and flu in early pregnancy. 29 cases of target DNA fragment were successful sequencing,there were 9 mutations, which caused amino acid changes in sites. The 9 effected mutations concentrated in 7 cases, FOXC2 gene mutation rate was 24.1%(7/29).Conclusion: Variety of factors during pregnancy can cause the increased incidence of CHD.FOXC2 gene mutations had close relationship.with CHD. The FOXC2 mutations of CHD patients caused change of encoding amino acids,so FOXC2 gene mutations had close relationship.with CHD.The site of FOXC2 gene in 216bp, 255bp and 505bp mutation common occurred in CHD patients and cardiac defect fetus,it proved that the three mutation sites were congenital heart disease mutation hot spots.
在胚胎发育过程中,受到环境、遗传等多种因素的影响,胎儿在形态、组织结构及生理功能上的发育受到影响,常发生胎儿流产、死胎或存在出生缺陷,给家庭、社会带来沉重的经济与心理负担。先天性发育缺陷是流产、死胎、死产和新生儿死亡的主要原因之一。我国近年出生缺陷发生率大约波动在11‰～18‰,是严重影响出生人口健康素质的因素。寻找先天性发育缺陷的确切病因,进一步揭示其发病机理,对于开展产前预防、诊断及干预,提高出生人口素质具有重要的意义。
人叉头框-C2基因是具有DNA-结合域的翼状螺旋转录因子家族中的一员,在进化上具有高度保守性。定位于16q22- 16q24,只包含一个单独编码的外显子,没有内含子,cDNA全长为1506bp。其编码的蛋白质共有494个氨基酸残基。已有动物实验证明,Foxc2基因在胚胎发育过程中有着重要的作用,敲除Foxc2基因的小鼠可在心血管、软骨组织、肾脏、主动脉弓及眼睛间质等多部位表现出发育异常。人的FOXC2已经被克隆出来,人类的FOXC2基因和小鼠Foxc2基因有95%以上的同源性。人类FOXC2基因与临床的关联性最早是在家族遗传性疾病淋巴水肿-双睫毛综合征中被确认,LD综合征是一种罕见的常染色体显性遗传病。临床特征是下肢水肿和双重睫毛,还有个体合并静脉曲张、先天性心脏病和上睑下垂等,对LD家族的遗传分析发现FOXC2基因的突变和LD综合征发病密切相关。在动物实验中发现Foxc2与淋巴管的发生、中轴骨骼的发育、心血管系统及泌尿系统的发育有关,然而,在人类胚胎发育过程中,该基因的分子生物学表现及功能状况尚不清楚,故对FOXC2在胚胎发生中的作用及与先天发育缺陷的关系等方面进行研究。
第1部分先天发育缺陷胎儿的类型分析
目的:分析了长春地区先天性发育缺陷的类型,为重点缺陷的预防提供理论依据。方法:收集长春市多家医院妇产科就诊的流产或引产死胎,伴发育缺陷胎儿73例。对明显的发育畸形进行记录。分析异常器官。结果:在73例先天性发育异常胎儿中,男性41例,女性32例。由于在一个胎儿可以发生多组织器官的畸形或缺陷,共发现了93个器官或组织发育畸形,致宫内死胎共32例。神经管异常47例,占全部发育异常胎儿的64.3%(47/73),占发育畸形的构成比例为50.5%(47/93)。心血管发育异常病例19例,占全部发育异常胎儿的26%(19/73);心血管发育异常死胎15例,心血管发育异常儿胎死宫内发生率为78.9%(15/19),占畸形胎儿死胎总数的46.9%(15/32)。结论:在73例先天性发育缺陷胎儿中,男性比例高于女性。神经管发育缺陷是长春地区最主要的先天发育缺陷。心血管发育异常是胎死宫内最主要原因,也是本地区主要的先天发育缺陷。发现与成人LD综合征相似的淋巴水肿胎儿。
第2部分FOXC2是人胚胎多器官发育重要的转录因子
目的:研究FOXC2是否参与人胚胎发生发育过程。方法:通过免疫组化方法分析了FOXC2在人胚胎发育过程中的作用。结果:FOXC2在人胚胎最早期的头部间充质发生发育过程中起作用。在肋骨软骨的生发中心肋软骨始基细胞核看到FOXC2蛋白强表达。心脏的大血管、主动脉全层、心室内膜及心室壁外层可见到FOXC2的表达。胚胎肾脏的髓质可见到FOXC2的表达。结论:FOXC2基因是中轴骨骼的发育过程中必不可缺少的转录因子;FOXC2在人胚胎心血管系统发生、发育过程中发挥重要的生物功效;人胚胎期肾脏的发育也需要FOXC2参与。
第3部分胎儿先天发育缺陷危险因素及FOXC2基因多态性分析
目的:了解先天发育缺陷的危险因素及FOXC2基因的变异与先天发育缺陷发生的关系。方法:对73例先天发育缺陷胎儿的相关危险因素进行调查、登记和分析。提取发育缺陷胎儿基因组DNA,通过PCR反应扩增出包含FOXC2 cDNA的目的片段,送检测序,进行基因多态性分析。结果:父母亲的不良生活习惯、家族发育缺陷遗传史、父母特殊工作史、特殊化学试剂接触史、未行孕前检查及孕早期未补充叶酸、维生素等与胎儿先天性发育缺陷的发生密切相关。对68例发育缺陷胎儿成功测序样本进行分析,共存在20个突变位点,其中引起编码氨基酸改变的突变点共15个。此15个有效突变位点集中在12个病例(包括神经管发育异常、心血管发育异常、淋巴水肿及多囊肾胎儿)中,FOXC2基因突变发生率为17.6%(12/68)。结论:孕期多种因素可以导致先天发育缺陷的发生率增加。基因变异分析发现了胚胎发育期神经管、心血管发育异常、淋巴水肿及多囊肾等先天发育缺陷胎儿存在FOXC2基因多点变异;胚胎期淋巴水肿胎儿显示了与成人LD综合征相似的高FOXC2基因突变率;胚胎期发育缺陷胎儿FOXC2基因的有效突变导致编码氨基酸改变,证明FOXC2基因变化与胎儿先天缺陷的发生密切相关。
第4部分先天性心脏病危险因素及FOXC2基因多态性分析
目的:了解先心病的危险因素及FOXC2基因的变异与先心病发生的关系。方法:对34例先心病患者的相关危险因素进行调查、登记和分析。提取先心病患者基因组DNA,通过PCR反应扩增出包含FOXC2 cDNA的目的片段,送检测序,进行基因多态性分析。结果:父母亲的吸烟、饮酒等不良生活习惯、父母特殊化学试剂接触史、家族发育缺陷遗传史、孕早期服药、孕早期感冒等均与CHD的发生有关联。成功测序29例先心病患者中,引起编码氨基酸改变的突变位点有9个,集中在7例患者中,有效突变率为24.1%(7/29)。结论:孕期多种不良因素可以导致先心病发病率的增加。CHD患者的FOXC2基因突变引起了编码氨基酸的改变,表明FOXC2的基因突变与CHD的发生密切相关;先心病患者与心脏畸形胎儿共同存在FOXC2基因216bp、255bp和505bp位点的突变,证明这三个突变位点是先心病的突变热点。
Mutation analysis of FOXC2 gene in congenital developmental defect
In embryonic development, by environmental, genetic and other factors, the fetus development of the appearance, structure and physiological function were affected, fetal abortion, stillbirth or birth defects often exist,it's a heavy economic and psychological burden to the family and society. Congenital developmental defects were large proportion mortality in the fetal and neonatal. it's a serious impact on quality of health diathesis. Find the exact cause of congenital defects, and further reveal its pathogenesis, it's great significance for prenatal prevention, diagnosis and intervention, and improve the quality of births.
Human forkhead box c2 (FOXC2),a member of the winged helix transcription factors family with DNA-binding domains, was evolutionarily highly conserved.The positiong was 16q22-16q24, it only Contained a single coding exon, no intron, the length of cDNA was 1506bp. The protein encoded 494 amino acid residues. Animal experiments have proved, Foxc2 gene in embryonic development played an important role. in gene knockout mice showed abnormalities in cardiovascular, cartilage, kidney, aortic arch and the eyes and other parts of the stroma.Human FOXC2 have been cloned, the human FOXC2 gene and the gene in mice Foxc2 had more than 95% homology.The first relevance of the human FOXC2 gene and clinical disease was confirmed in a hereditary disease-lymphedema -distichiasis syndrome.LD syndrome was a rare autosomal dominant genetic disease. The clinical characteristics were lower limb edema and double eyelashes, and the individual merge varicose veins, congenital heart disease and ptosis.The genetic analysis of LD family found that the FOXC2 gene mutations and LD syndrome were closely related. In animal experiments,it has found that Foxc2 was related with lymphangiogenesis, the development of axial skeleton, cardiovascular system and urinary system.However, in human embryonic development, the gene expression of molecular biology and functional status is not clear, So we did the the research,we want to know the relationship with FOXC2's role in embryogenesis and congenital developmental defects.
PartⅠAutopsy type analysis of congenital developmental defects fetal
Objective: Analysis of congenital developmental defects in Changchun, and provide the theoretical basis on the prevention of point defects.Methods: Collected 73 cases of developmental defects fetus that were abortion and induced in Obstetrics and Gynecology department of several hospital in Changchun. We recorded obvious malformations and analysis of abnormal organs. Results: In the 73 cases of congenital abnormalities fetus, male were 41 cases, female were 32 cases. Since a fetus could occur malformations or defects in several tissues and organs, 93 cases of malformations were found in different organ and tissue,they caused 32 cases intrauterine fetal death. The largest number of malformations were neural tube defects, 47 cases. accounting for 64.3%(47/73)of fetal abnormalities,the composition ratio of total malformations was 50.5%(47/93).The number of cardiovascular abnormalities were 19, accounting for 26% (19/73)of fetal abnormalities,the composition ratio of total malformations was 20.4% (19/93). Stillbirth of cardiovascular abnormalities were 15 cases, cardiovascular abnormalities fetal death rate was 78.9% (15/19), accounting for the total number of abnormal stillbirth 46.9% (15/32).Conclusion: In 73 cases of congenital developmental defects fetus, the proportion of male was more than female. Neural tube defects was the most important congenital developmental defects in Changchun area. Cardiovascular abnormalities in this region was also the major congenital developmental defects,it was the main reason caused intrauterine fetal death.We found lymphedema fetus similar to adult LD syndrome.
PartⅡFOXC2's a important transcription factor in the human embryonic development of many organs
Objective: To know if FOXC2 was involved in the development of human embryos. Methods:We analyzed FOXC2's role in the human embryonic development by Immunohistochemical methods.Results: In the human embryo,FOXC2 first occurred in the head mesenchyme. Then In the costal rib cartilage primordial germinal center found strong expression of FOXC2 protein in the nucleus. We could found FOXC2 expression in the the great vessels of heart, whole layer of aortic,the ventricular endocardium and the ventricular outer wall. Embryonic kidney medulla also had FOXC2 expression. Conclusion: FOXC2 gene was the indispensable transcription factor in the process of development of central axial skeleton; FOXC2 played an important biological effect in the process of development of human embryonic cardiovascular system; The development of human embryonic kidney also need FOXC2 participation.
PartⅢThe analysis of risk factors for fetal congenital developmental defects and FOXC2 gene polymorphism
Objective: To understand the relationship of risk factors with congenital developmental defects ,and FOXC2 gene mutation with congenital developmental defects.Methods: The risk factors were investigated, registed and analysis of 73 cases congenital developmental defects fetus.Extract their genomic DNA, amplified FOXC2 cDNA fragment by PCR,and inspect sequencing,then analysis the genetic polymorphism. Results: The occurrence of congenital defects fetus were closely related with parents' bad habits, family heredity history of developmental defects,parents' special work history, history of exposure to specific chemical agents, no progestation examination and without supply folic acid and vitamins in early pregnancy. 68 cases of target DNA fragment were successful sequencing,there were 20 mutations, which caused 15 amino acid changes in sites. The 15 effected mutations concentrated in 12 cases (including the neural tube defects, cardiovascular abnormalities, fetal lymphedema and polycystic kidney fetus), FOXC2 gene mutation rate was 17.6% (12/68). Conclusion: Gene mutation analysis found FOXC2 multiple mutation spots in embryogenesis congenital defects with neural tube defects, cardiovascular dysplasia,lymphedema and polycystic kidney.The embryonic period lymphedema fetus showed similar high FOXC2 mutation rate to adult LD syndrome.The FOXC2 mutations of embryonic developmental defectfetus caused change of encoding amino acids,so FOXC2 gene mutations had close relationship.with birth defects.
PartⅣThe analysis of risk factors for congenital heart disease and FOXC2 gene polymorphism
Objects: To understand the relationship of risk factors with congenital heart disease,and FOXC2 gene mutation with congenital heart disease.Methods: Collected 34 children's myocardium with congenital heart disease in cardiac surgery of the First Hospital of Jilin University.The risk factors were investigated, registed and analysis of 34 cases CHD patients.Extract their genomic DNA, amplified FOXC2 cDNA fragment by PCR,and inspect sequencing,then analysis the genetic polymorphism. Results: The occurrence of CHD were closely related with parents' bad habits(smoking and drinking), history of exposure to specific chemical agents, family heredity history of developmental defects, drug administration and flu in early pregnancy. 29 cases of target DNA fragment were successful sequencing,there were 9 mutations, which caused amino acid changes in sites. The 9 effected mutations concentrated in 7 cases, FOXC2 gene mutation rate was 24.1%(7/29).Conclusion: Variety of factors during pregnancy can cause the increased incidence of CHD.FOXC2 gene mutations had close relationship.with CHD. The FOXC2 mutations of CHD patients caused change of encoding amino acids,so FOXC2 gene mutations had close relationship.with CHD.The site of FOXC2 gene in 216bp, 255bp and 505bp mutation common occurred in CHD patients and cardiac defect fetus,it proved that the three mutation sites were congenital heart disease mutation hot spots.
引文
[1]Lai E, Clark KL, Burley SK, et al. Hepatocyte nuclear factor 3/fork head or“winged helix”proteins: A family of transcription factors of diverse biologic function [J]. Proc. Natl. Acad. Sci. USA,1993,90: 10421–10423.
[2]Costa RH. Hepatocyte nuclear factor 3/forkhead protein family: mammalian transcription factors that pocess divergent cellular expression patterns and binding specificities [M]. In Tronche F, and Yaniv M(eds.), Liver Gene Expression, R.G.Landes company, Austin, TX. 1994.
[3]Kaufmann E, Kn?chel W. Five years on the wings of fork head [J]. Mech Dev, 1996, 57: 3–20.
[4]Katoh M.Human FOX gene family[J].Int J Oncol,2004,25(5):1495-1500.
[5]Susan LD, Rebecca LH, Robert PE, et al. Glover FOXC2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome[J]. Gene Expression Patterns, 2004, 4: 611-619.
[6]Miura N, Iida K, Kakinuma H, et al. Isolation of the mouse (MFH-1) and human (FKHL-14) mesenchyme fork head–1 gene reveals conservation of their gene and protein structures [J]. Genomics,1997, 41(3):489-492.
[7]Kaestner KH, Bleckmann SC, Monaghan AP, et al. Clustered arrangement of winged helix genes fkh-6and MFH-1:possible implications for mesoderm development [J].Development, 1996, 122(6):1751-1758.
[8]Wilm B,James RG,Schultheiss TM,Hogan BL.The forkhead genes,Foxc1 and Foxc2,regulate paraxial versus intermediate mesoderm cell fate[J].Dev Biol,2004, 271(1):176-189.
[9]Miura N, Wanaka A, Tohyama M, et al. MFH-1, a new member of the fork head domain family is expressed in developing mesenchyme[J]. FEBS Lett,1993,326(1-3): 171-176.
[10]Baldwin AL,Ferrer P,Rozum JS,et al.Regulation of water balance between blood and lymph in the frog,Ranapipiens[J].Lymphology, 1993, 26(1):4-18.
[11]Qiao R,Wang H,YanWL,et al.Hyaluronan in extracellularmatrix is a determinant ofendothelial barrier[J].Am J Physiol,1995,269:110-117.
[12]Makinen T,Norrmen C,Petrova TV.Molecular mechanisms of lymphatic vascular development[J].Cell Mol Life Sci,2007,64(15):1915-1929
[13]王炜.整形外科学[M].浙江:科学技术出版社.1999,1534-1542.
[14]Tammela T,Petrova TV,Alitalo K.Molecular lymphangiogenesis:new players[J]. Trends Cell Biol,2005,15(8):434-441.
[15]Ferrell RE,Kimak MA,Lawrence EC,et al.Candidate gene analysis in primary lymphedema[J].Lymphat Res Biol,2008,6(2):69-76.
[16]Wu X,Liu NF.FOXC2 transcription factor:a novel regulator of lymphangio- genesis[J].Lymphology,2011,44(1):35-41.
[17]Dagenais SL,Haitsough RL,Erickson RP,et al.Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndro- me[J].Gnen Expr Patterns,2004,4(6): 611-619.
[18]Gombos Z, Xu X, Chu CS, Zhang PJ, Acs G. Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix [J].Clin Cancer Res 2005;11(23):8364-8371.
[19]Mellor RH,Tate N,Stanton AW,et al.Mutations in FOXC2 in human lymphedema distichiasis syndrome) [J].J Vase Res,2011,48(5):397-407.
[20]Petrova TV, Karpanen T, Norrme′n C, Mellor R, Tamakoshi T, Finegold D, et al.Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis [J]. Nat Med 2004;10(9):974-981.
[21]Shimoda H, Bernas MJ, Witte MH. Dysmorphogenesis of lymph nodes in Foxc2 haploinsufficient mice[J]. Histochem Cell Biol. 2011 Jun;135(6): 603-13.
[22]田丽娜,邓伟国,邹积艳,马莉,丁言良,宋文龄,付艳.叉头框C2在人胚淋巴管发生过程中的表达[J].解剖学报,2008,39(6):886-889.
[23]Fang J, Dagenais SL, Erickson RP, et al. Mutations in FOXC2(MFH21),a forkhead family transcription factor, are responsible forthe hereditary lymphedema-distichiasis syndrome[J].An J Hum Genet, 2000,67(6):1382 -1388.
[24]Yabuki S,Kikuchi S,Ikegewa S.Spinal extradural arachniod cysts associated withdiatichiasis and lymphedema[J].Am J Med Genet A,2007,143 (8):884-887.
[25]Mansour S, Brice GW, Jeffery S, Mortimer P. Lymphedema-Distichiasis Syndrome. [J].Gene Reviews,2007,8(2):1993-2005.
[26]Raboulsi EI,Al-Khayer K,Matsumoto M,et al.Lymphedema-distichiasis syndrome and FOXC2 gene mutation [J]. Am J Ophthalmol, 2002, 134(4): 592-624.
[27]Retrova TV,Karpanen T,Norrmen C,et al.Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis[J]. Nat Med,2004,10(9):974-981.
[28]Brice G, Mansour S, Bell R, et al. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24 [J]. J Med Genet, 2002, 39(7): 478-483.
[29]Erickson R P, Dagenais S L, CaulderM S, et al. Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutation [J]. J Med Genet, 2001,38(11):761-766.
[30]Bell R,Brice G,Child A H,et al.Analysis of lymphoedema-distichiasis families for FOXC2 mutations reveals small insertions and deletions throughtout the gene[J]. Hum Genet, 2001,108(6):546-551.
[31]Berry FB,Tamimi Y,Carle MV,et al. The establishment of a predictivemutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis[J]. Hum Mol Genet, 2005,14 (18):2619-2627.
[32]ELIAS I, TRABOULSI, KHOULOUD AL-KHAYER, MASAYUKI MATSUMOTO, et al. Lymphedema–Distichiasis Syndrome and FOXC2 Gene Mutation[J]. AMERICAN JOURNAL OF PHTHALMOLOGY.2002,134(4):592-596.
[33]Arash Ghalamkarpour,Christian Debauche,Eric Haan, BMedSc, et al. Sporadic In Utero Generalized Edema Caused by Mutations in the Lymphangiogenic Genes VEGFR3 and FOXC2[J]. THE JOURNAL OF PEDIATRICS. 2009,155(1):90-93.
[34]Fauret AL, Tuleja E, Jeunemaitre X, Vignes S. A novel missense mutation and two microrearrangements in the FOXC2 gene of three families with lymphedema-distichiasissyndrome[J]. Lymphology. 2010 Mar;43(1): 14-18.
[35]Robert P Erickson,Susan L Dagenais,Mark S Caulder, et al.Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations[J].J Med Genet,2001:38: 761-766
[36]David N,Finegold,Mark A Kimak, et al.Truncating mutations in FOXC2 cause muitiple lymphedema syndromes[J].Human Molecular Genetics,2001, 10(11):1185-1189.
[37]Fauret AL,Tuleja E,Jeunemaitre X,et al.A novel missense mutation and two microrearrangements in the FOXC2 gene of three families with lymphedema- distichiasis syndrome[J].Lymphology,2010,43(1):14-18.
[38]Fabretto A,Shardlow A,Faletra F,et al.A case of lymphedema- distichiasis syndrome carrying a new de novo frameshift FOXC2 mutation[J].Ophthalmic Genet,2010, 31(2):98-100.
[39]Rriederman BM, Myloyde TL, Witte MH, et al. FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome [J]. Hum Mol Genet, 2003, 12(10): 1179-1185.
[40]Agenais SL, Hartsough RL, Erickson RP, et al. Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema–distichiasis syndrome [J]. Gene Expression Patterns, 2004, 4(6): 611-619.
[41]Mellor RH, Tate N, Stanton AW, Hubert C, M?kinen T, Smith A, Burnand KG, Jeffery S, Levick JR, Mortimer PS. Mutations in FOXC2 in humans (lymphoedema distichiasis syndrome) cause lymphatic dysfunction on dependency. [J]. J Vasc Res. 2011;48(5):397-407.
[42]Kriederman BM, Myloyde TL,Witte MH,et al.FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome [J].Hum Mol Genet, 2003, 12 (10):1179-85.
[43]Mellor RH, Brice G, Stanton A.WB, et al. Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb [J]. Journal of Vascular Surgery 2007,:608-612
[44]Russell H. Mellor, Glen Brice, Anthony W.B. Stanton, Jane French, , et al.Mutations inFOXC2 Are Strongly Associated With Primary Valve Failure in Veins of the Lower Limb [J]. Circulation 2007;115:1912-20.
[45]Wu X, Liu NF. FOXC2 transcription factor: a novel regulator of lymphangio- genesis [J].Lymphology.2011 Mar;44(1):35-41.
[46]Bruyn G, Casaer A, Devolder K, Van Acker G, Logghe H, Devriendt K, Cornette L. Hydrops fetalis and pulmonary lymphangiectasia due to FOXC2 mutation: anautosomal dominant hereditary lymphedema syndrome with variable expression[J]. Eur J Pediatr. 2011,Sep,15, [Epub ahead of print].
[47]Kume T, Jiang H, Topczewska JM, et al. The murine winged helix transcription factors, Foxc1 and FOXC2, are both required for cardiovascular development and somitogenesis [J]. Genes Dev, 2001,15(18): 2470-2482.
[48]Dang J M,Dagenais S L,Erickson R P,et al. Mutations in Foxc2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet, 2000,67(6):1382-1388.
[49]付艳,邓伟国,李玉林等.叉头框c2在中轴骨骼发育过程中的作用.中国病理生理杂志[J].2004,20(11):1966-1971.
[50]Wotton KR, Shimeld SM. Analysis of lamprey clustered Fox genes: Insight into Fox gene evolution and expression in vertebrates[J]. Gene. 2011 Aug 31,[Epub ahead of print].
[51]刘珉,刘伟.FOXC2的研究进展[J].上海第二医科大学学报, 2005,7:757 -760.
[52]Park SJ, Gadi J, Cho KW, Kim KJ, Kim SH, Jung HS, Lim SK.The forkhead transcription factor Foxc2 promotes osteoblastogenesis via up-regulation of integrinβ1 expression[J]. Bone. 2011 Sep;49(3):428-38.
[53]Kriederman BM, Myloyde TL, Witte MH, Dagenais SL, Witte CL, Rennels M,Bernas MJ,et al.FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome. Hum Mol Genet, 2003,12 (10):1179 -1185.
[54]Timur AA,Driscoll DJ,Wang Q.Biomedicine and diseases:the Klippel- Trenaunay syndrome,vascular anomalies and vascular morphogenesis[J].Cell Mol Life Sci,2005, 62(13):1434-1447.
[55]Lamont RE,Childs S.MAPping out arteries ang veins[J].Sci STKE,2006, 2006 (355):39-45.
[56]Ng MY,Andrew T,Spector TD,et al.Lingage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy,unselected sibling pairs[J].J Med Genet,2005, 42(3):235-239
[57]Bahuau M,Houdayer C,Tredano M,et al.FOXC2 truncating mutation in distichiasis, lymphedema, and cleft palate [J].Clin Genet., 2002, 62(6): 470-473.
[58]Brooks BP,Dagenais SL,Nelson CC,et al.Mutation of the FOXC2 gene in familial distichiasis [J].J AAPOS, 2003, 7(5):354-357.
[59]Kanzaki-Kato N,Tamakoshi T,Fu Y,et al.Poles of forkhead transcri- ption factor Foxc2(MFH-1) and endothelin receptor A in cardiovascular morphogenesis[J]. Cardiovasc Res,2005,65(3):711-718.
[60]Li D,Yan D,Liu W,et al.Foxc2 overexpression enhances benefit of endothelial progenitor cells for inhibiting neointimal formation by promoting CXCR4-dependent homing[J].J Vasc Surg,2011,53(6):1668-1678.
[61]Yu S,Shao L,Kilbride H,et al.Haploinsufficiencies of FOXC1and FOXC2 genes associated with lethal alveolar capillary dysplasia and congenital heart disease[J].Am J Med Genet A,2010,152A(5):1257-1262.
[62]Ramsey A. Saleem, Sharmila Banerjee-Basu, Fred B. Berry, et al. Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1. Human Molecular Genetics, 2003,22;2993-3005.
[63]Seo S,Fujita H,Nakano A.The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development [J].Dev Biol,2006,294(2):458-470.
[64]Seo S,Kume T.Forkhead transcription factors,Foxc1 and Foxc2,are required for the morphogenesis of the cardiac outflow tract[J].Dev Biol,2006,296(2):421-436.
[65]Kume T,Deng K,Hogen BL.Murine forkhead/winged helix genes Foxc1(Mf1) and Foxc2(Mf2) are required for the early organogenesis of the kidney and urinary tract[J].Development,2000,127(7):1387-1395.
[66]Takemoto M,He L,Norlin J,et al.Large-scale identification of genes implicated in kidney glomerulus development and function[J].EMBO J, 2006,25(5):1160-1174.
[67]White JT,Zhang B,Cerqueira DM,et al.Notch signaling,wt1 and foxc2 are key regulators of podocyte gene regulatory network in Xenopus[J]. Development,2010, 137(11) 1863-1873.
[68]Mitchell EK,Taylor DF,Woods K,et al.Differential gene expression in the developing mouse ureter[J].Gene Expr Patterns, 2006,6(5):519-538.
[69]Bergman RN, Van Citters GW, Mittelman SD, et al. Central role of the adipocyte in the metabolic syndrome[J]. J Investig Med, 2001, 49(1): 119-126.
[70]Morrison RF, Farmer SR. Hormonal signaling and transcriptional control of adipocyte differentiation [J]. J Nutr, 2000, 130(12): 3116S-3121S.
[71]Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ [J]. Proc Nutr Soc, 2001,60(3): 329-339.
[72]Rajala MW, Scherer PE. Minireview: The adipocyte--at the crossroads of energy homeostasis, inflammation, and atherosclerosis[J]. Endocrinology, 2003, 144(9): 3765-3773.
[73]Prins JB and O'Rahilly S. Regulation of adipose cell number in man [J]. Clin Sci (Lond), 1997, 92(1): 3-11.
[74]Tong Q, Dalgin G, Xu H, et al. Function of GATA transcription factors in preadipocyte-adipocyte transition [J]. Science, 2000, 290(5489):134 -138.
[75]Moldes M, Zuo Y, Morrison RF, et al. Peroxisome-proliferators -activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis [J]. Biochem J, 2003, 376(Pt 3): 607-613.
[76]Davis KE, Moldes M, Farmer SR. The forkhead transcription factor FoxC2 inhibits white adipocyte differentiation [J]. J Biol Chem, 2004,279(41): 42453-42461.
[77]Isabelle Gerin,Guido T.Bommer,Martin E.Lidell,et al.On the Role of FOX Transcription Factors in Adipocyte Differentiation and Insulin- stimulated Glucose Uptake[J].J Biol Chem,2009,284(16):10755–10763.
[78]Krings A,Rahman S,Huang S,et al.Bone marrow fat has brown adipose tissuecharacteristics,which are attenuated with aging and diabetes[J]. Bone,2011,Jun,24,[Epub ahead of print].
[79]Davis KE,Moldes M,Farmer SR.The forkhead transcription factor Foxc2 inhibits white adipocyte differentiation[J].J Biol Chem,2004,279(41): 42453-42461.
[80]Jason K. Kim,Hyo-Jeong Kim,So-Young;Park,et al. Adipocyte-Specific Overexpression of FOXC2 Prevents Diet-Induced Increases in Intramuscular Fatty Acyl CoA and Insulin Resistance[J].Diabetes,2005,54:1657-1663.
[81]Shaat N,Lernmark A,Karlsson E,et al.A variant in the transcription factor 7-like 2(TCF7L2) gene is associated with an increase risk of gestational diabetes mellitus [J].Diabetologia,2007,50(5):972-979.
[82]Komulainen,Kati;Peltonen,et al.The Effect of Variants of Familial Combined Hyperlipidemia Candidate Genes, USFL and FOXC2, on Cardiova- scular Atherosclerotic Lesions[J].Circulation,2005,46(4):187-194.
[83]Lidell ME,Seifert EL,Westergren R,et al.The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function[J].Diabetes, 2011,60(2):427-435.
[84]Kovacs P, Lehn-Stefan A, Stumvoll M, et al. Genetic variation in the human winged helix/forkhead transcription factor gene FOXC2 in Pima Indians. Diabetes,2003,52: 1292-1295.
[85]Yanagisawa K, Hingstrup Larsen L, Andersen C, et al. The FOXC2 -512C>Tvariant is associated with hypertriglyceridaemia and increased serum C-peptide in Danish Caucasian glucose-tolerant subjects.Diabetologia, 2003, 46 :1576-1580.
[86]Xue Y,Cao R,Nilsson D,Chen S,Westergren R,Hedlund EM,Martijn C, Rondahl L,Krauli P,Walum E,Enerb?ck S,Cao Y.FOXC2 controls Ang-2 expression and modulates angiogenesis, vascular patterning, remodeling, and functions in adipose tissue[J].Proc Natl Acad Sci U S A,2008,105 (29):10167–10172.
[87]Huber, M. A., Kraut, N., & Beug, H.. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Current Opinion in Cell Biology, 2005, 17:1–11.
[88]Hader C,Marlier A,Cantley L.Mesenchymal-epithelial transition in epithelial response to injury:the role of Foxc2[J].Oncogene,2010,29(7): 1031-1040.
[89]Mani SA,Yang J,Brooks M,et al.Mesenchyme forkhead 1(FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers[J].Proc Nat1 Acad Sci USA,2007,104(24):10069-10074.
[90]Nishida N,Mimori K,Yokobori T,et al.FOXC2 is a novel prognostic factor in human esophageal squamous cell carcinoma[J].Ann Surg Oncol, 2011,18(2):535-542.
[91]Saxena M,Stephens MA,Pathak H,et al.Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters[J].Cell Death Dis,2011,2(6):179-184.
[92]Sano H,Leboeuf JP,Novitskiy SV,et al.The Foxc2 transcription factor regulates tumor angiogenesis[J].Biochem Biophys Res Commun,2010,392(2): 201-206
[93]Gould DB,Smith RS,John SW.Anterior segment development relevant to glaucoma [J].Int Dev Biol,2004,48(8-9):1015-1029.
[94]王彦,于青.山东省出生缺陷发生率与婚检率的关系[J].泰山医学院学报,2010,31(10):779-780.
[95]马二铃,张敬如,张国华,陈景伟,张彦玲.石家庄地区2005至2009年城乡围产儿出生缺陷临床分析[J].河北医药,2010,32(24):3558-3559.
[96]曾萼.广西壮族自治区以人群为基础的出生缺陷监测结果分析[J].中国妇幼保健,2010,25(25):3587-3588.
[97]刘凯波,潘迎,丁辉.2006年北京市出生缺陷监测数据分析[J].中国优生与遗传杂志,2007,15(6):95-97.
[98]Hansen M,Sullivan E,Jequier AM,Burton P,Junk S,Yovich J,Bower C. Practitioner reporting of birth defects in children born following assisted reproductive technology: Does it still have a role in surveillance of birth defects? Human[J].Reproduction, 2007,22(2): 516– 520.
[99]Shaer C M,Chescheir N,Schulkin J.Myelomeningocele: A Review of the Epidemiology, Genetics, Risk Factors for Conception, Prenatal Diagnosis, and Prognosis for Affected Individuals[J].Obstet &Gynecol Survey,2007, 62(7):471-479.
[100]Evans M I,Llurba E,Landsberger EJ,O’Brien J E,Harrison H H.Impact of Folic Acid Fortification in the United States: Markedly Diminished High Maternal Serum Alpha-Fetoprotein Values[J].Obstet &Gynecol.2004,103(3): 474-479.
[101]Ford N,Calmy A,Mofensen L.Safety of efavirenz in first-trimester of pregnancy: an updated systematic review and meta-analysis[J].AIDS,2011, 00(00):1-4.
[102]乐杰.妇产科学[M].第7版.北京:人民卫生出版社,2008,132.
[103]Stauffer NR,Murphy K.Prenatal diagnosis of congenital heart disease: the beginning[J].Crit Care Nurs Q,2002,25(3):1-7.
[104]Allan LD.Fetal cardic anomalies[J]. Prog Pediatr Cardiol,1996(5): 103-112.
[105]卢媛,李莹,刘婷婷.武昌地区13家助产机构2006至2009年围生儿出生缺陷分析[J].中华妇幼临床医学杂志(电子版),2011,7(2):133-136.
[106]蒲柳艳,吴金华.浙江省舟山市定海区出生缺陷监测与父母相关因素研究[J].疾病监测,2010,25(10):806-892.
[107]崔慧芳.17188例围产儿出生缺陷监测分析及干预措施探讨[J].中国优生与遗传杂志,2010,18(6):110-111.
[108]胡继宏,赵燚,刘兰,吴海鹰,张涛,宋晨阳.宁夏回族自治区0~1岁婴儿出生缺陷发生率普查情况分析[J].中国计划生育学杂志,2010,2:92-94.
[109]Cabrera RM,Hill DS,Etheredge AJ,et al. Investiations into the etiology of neural tube defects [J]. Birth Defects Res C Embryo Today, 2004,72(4):330-344.
[110]代礼,朱军,周光萱,等.1996～2000年全国神经管缺陷的动态监测[J].中华预防医学杂志. 2002,36(6):402-405.
[111]Ford N,Calmy A,Mofensen L.Safety of efavirenz in first-trimester of pregnancy: an updated systematic review and meta-analysis[J].AIDS, 2011, Sep,13,[Epub ahead of print].
[112]Bruneau BG.Mouse model of cardia chamber formation and congenital heart disease[J]. Trends in Genetics,2002,18,(6):15-20.
[113]胡昕婴,史剑慧,葛均波.心肌分化的调控[J].国外医学遗传学分册,2003,26:209-212.
[114]Brown CO,Chi X,Garcia-Gas E,et al.The cardiac determination factor, Nkx2-5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer[J].Jboil Chem,2004,279(11):10659-10669.
[115]Lin CR,Kioussi C,O'Connell S,Briata P,Szeto D,Liu F,Izpisúa-Belmonte JC, Rosenfeld MG.Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis[J].Nature,1999, 401(6750):279-282.
[116]Srivastava D,Thomas T,Lin Q,Kirby ML,Brown D,Olson EN.Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND[J].Nat Genet,1997,16(2):154-160.
[117]Grewal J,Carmichael SL,Ma C,Lammer EJ,Shaw GM.Maternal periconcep- tional smoking and alcohol consumption and risk for select congenital anomalies[J]. Birth Defects Res A Clin Mol Teratol,2008,82(7):519-526.
[118]Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H, Gravel RA, Rozen R. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida[J].Mol Genet Metab,1999,67(4):317-23.
[119]Vieira AR, Meira R, Modesto A,et al. MSX1, PAX9, and TGFA contribute to tooth agenesis in humans[J].J Dent Res, 2004,83(9):723- 727.
[120]Kume T.Foxc2 transcription factor: a newly described regulator of angiogenesis[J]. Trends Cardiovasc Med,2008,18(6):224-228.
[121]Bard JB,Lam MS,Aitken S.Bioinformatics approach for identifying candidate transcriptional regulators of mesenchyme-to-epithelium transitions in mouse embryos [J].Dev Dyn,2008,237(10):2748-2754.
[122]上海第一医学院.组织胚胎学[M].北京:人民卫生出版社,1978,373-376.
[123]刘斌,高英茂.人体胚胎学[M].北京:人民卫生出版杜,1996, 366-371.
[124]Kaestner KH,Bleckmann SC,Monaghan AP,Schl?ndorff J, Mincheva A, Lichter P and Schütz G. Clustered arrangement of winged helix genes fkh-6and MFH-1: possible implications for mesoderm development[J]. Development,1996,122: 1751-1758.
[125]Kirby ML,Waldo KL.Neural crest and cardiovascular patterning [J].Circ Res, 1995,77(2):211-215.
[126]Le Lievre CS,Le Douarin NM.Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos[J].J Embryol Exp Morphol,1975,34(1):125-154.
[127]Larsen WJ.人类胚胎学Human Embryology(英文版)[M].北京:人民卫生出版社-Health Science Asia Elsevier Science,2002:196-222.
[128]Mitchell EK,Taylor DF,Woods K,Davis MJ,Nelson AL,Teasdale RD,Grimmond SM,Little MH,Bertram JF,Caruana G.Differential gene expression in the developing mouse ureter[J].Gene Expr Patterns,2006, 6(5):519-538.
[129]Finegold DN,Kimak MA,Lawrence EC,Levinson KL,Cherniske EM,Pober BR, Dunlap JW,Ferrell RE.Truncating mutations in FOXC2 cause multiple lymphedema syndromes [J].Hum Mol Genet,2001,10(11):1185-1189.
[130]Smith RS,Zabaleta A,Kume T,Savinova OV,Kidson SH,Martin JE, Nishi- mura DY,Alward WL,Hogan BL,John SW.Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development[J].Hum Mol Genet,2000,9 (7):1021-1032.
[131]Melve KK, Skj?rven R. Families with birth defects: is birth weight of nonmalformed siblings affected? [J].Am J Epidemiol,2002,155:932–940.
[132]Lie RT, Wilcox AJ, Skj?rven R. Survival and reproduction among males with birth defects and risk of recurrence in their children [J].JAMA, 2001,285:755–760.
[133]Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A,Taylor DJ.Childhood Outcomes After Prescription of Antibiotics to Pregnant Women With Spontaneous Preterm Labour: 7-Year Follow-Up of the ORACLE II Trial [J].Lancet 2008;372: 1319–1327.
[134]付丽杰,阎云,张红恩.畸胎学[M].上海:上海科技教育出版社,1996,18- 157.
[135]Brown CO,Chi X,Garcia-Gas E,et al.The cardiac determination factor, Nkx2-5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer [J].J boil Chem,2004,279(11):10659-10669.
[136]谌琛,惠汝太.心脏特异转录因子及其对心脏发育和心脏基因的调控[J].中国分子心脏病学杂志,2005,5(3):561-565.
[137]Shiratori H,Yashiro K,Shen MM,Hamada H.Conserved regulation and role of Pitx2 in situs-specific morphogenesis ofvisceral organs[J]. Development,2006,133(15):3015-25.
[138]Lin CR,Kioussi C,OConnell S,et al.Pitx2 regulates lung asymmetry, cardiacpositioning and pituitary and tooth morphogenesis[J].Nature, 1999,401:279-282.
[139]Van Tuyl M,Liu J,Groenman F,et al.Iroquois genes influence proximo-distal morphogenesis during rat lungdevelopment[J].Am J Physiol Lung Cell Mol Physiol,2006,290(4):L777-L789.
[140]Hiroyuki Yamagishi,Eric N.Olson, Deepak Srivastava.The basic helix-loop-helix transcription factor, dHAND, is required for vascular development[J].The Jounal of Clinical Investigation, 2000,105:261-270.
[141]Tevosian S, Deconinck A, Tanaka M, et al.FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and Development of coronary vessels from epicardium[J].Cell,2000,101: 729-39.
[142]Ota K G,Fujimoto S,Oisi Y,Kuratani S.Identification of vertebra-like elements and their possible differentiation from sclerotomes in the hagfish[J].Nat Commun,2011, 28(2):373-378.
[143]Kume T, Jiang H, Topczewska JM, et al.The murine winged helix transcription factors, Foxc1 and FOXC2, are both required for cardiovascular development and somitog- enesis [J]. Genes Dev, 2001, 15(18):2470-2482.
[144]Sholto-Douglas-Vernon C, Bell R, Brice G, et al. Lymphoedema- distichiasi and FOXC2:unreported mutations, de novo mutation estimate, families without coding mutation[J].2005, 117: 238-242.
[145]罗美瑜.我国出生缺陷的现状及干预[J].海峡预防医学杂志,2006,12(5): 1-2.
[146]任太芳,素芳.新乡地区10506例围产儿中先天畸形及有关致畸因素的分析[J].中国优生与遗传杂志, 2005,13(1):100-113.
[147]胡荣华,杜玉开.武汉市围产儿先天畸形流行状况及影响因素研究[J].医学与社会, 2005,18(1):7-11.
[148]李颖,杨柳,杨文方.出生缺陷的相关因素[J].中国计划生育学杂志,2010,12(183): 755-757.
[149]白亚娜,屈燕,胡晓斌.出生缺陷致病因素的多因素分析[J].中国妇幼保健, 2004,19(5):44-46.
[150]ICBDMS1 Quarterly report of International Clearinghouse for Birth Defects Monitoring [J]. Systems, 3rd quarter July-August 2000. Roma Icbdms,2001.2-5.
[151]常利利.323例新生儿先天畸形相关因素的临床研究.吉林大学硕士学位论文,2008年.
[152]王玮,许伟,郑亚军,周宝森.先天畸形危险因素的病例对照研究[J].中国儿童保健杂,2007,15(4):403-405.
[153]Wotton KR,Shimeld SM.Analysis of lamprey clustered Fox genes: Insight into Fox gene evolution and expression in vertebrates[J]. Gene,2011,489(1):30-40.
[154]Park SJ,Gadi J,Cho KW,Kim KJ,Kim SH,Jung HS,Lim SK.The forkhead transcription factor Foxc2 promotes osteoblast ogenesis via up-regulation of integrinβ1 expression[J].Bone,2011,49(3):428-438.
[155]Mellor,Russell H,Brice,Glen,Stanton,,Anthony W B,et al.Mutations in FOXC2 Are Strongly Associated With Primary Valve Failure in Veins of the Lower Limb[J]. Circulation,2007,115:1912-1920.
[156]付艳,邓伟国,李艺扬等.叉头框-C2基因在主动脉弓发育过程中的作用[J].生物化学与生物物理进展,2003,30(5):726-731.
[157]De Bruyn G,Casaer A,Devolder K,Van Acker G,Logghe H,Devriendt K,Cornette L.Hydrops fetalis and pulmonary lymphangiectasia due to FOXC2 mutation: an autosomal dominant hereditary lymphedema syndrome with variable expression[J].Eur J Pediatr,2011,Sep 15,[Epub ahead of print].
[158]Stauffer NR,Murphy K.Prenatal.diagnosis f congenital heart disease: the beginning [J].Crit Care Nurs Q,2002,25(3):1-7.
[159]Allan LD.Fetal cardic anomalies[J].Prog Pediatr Cardiol,1996(5): 103-112.
[160]庄依亮.妊娠合并先天性心血管疾病.曹泽毅.中华妇产科学[M].北京:人民卫生出版社,1999,452-465.
[161]Marino B,Digilio MC.Congenital Heart Disease and Genetic Syndromes: Specific Correlation Between Cardic Phenotype and Genotype[J]. Cardiovasc Pathol,2000,9(6): 303-315.
[162]田中誠 ,北徹.心臓の発生と先天性心疾患のメカニズム[J].実験医学,2000,18(16):2280-2285.
[163]McFadden DG, Charite J, Richardson JA, et al. A GATA-dependent right ventricular enhancer controls dHAND transcription in the developing heart[J]. Development. 2000,127(24):5331-5341.
[164]Liu ZP, Nakagawa O, Nakagawa M, et al CHAMP, a novel cardiac-specific helicase regulated by MEF2C[J].Dev Biol. 2001,234(2):497-509.
[165]Lo CW, Wessels A.Cx43 Gap Junctions in Cardiac Development[J]. TCM, 1998, 9(6):264-269
[166]Junker R, Kotthoff S, Vielhaber H, Halimeh S, Kosch A, Koch HG, Kassenbohmer R, Heineking B, Nowak-Gottl U. Infant methylenetetrahydro- folate reductase 677TT genotype is a risk factor for congenital heart disease[J]. Cardiovasc Res. 2001,51(2):251-254.
[167]Lindsay EA, Baldini A. Congenital heart defects and 22q11 deletions: which genes count[J]? Mol Med Today. 1998,4(8):350-357.
[168]Schuring-Blom GH, Boer K, Knegt AC, et al. Trisomy 13 or 18 (mosaicism) in first trimester cytotrophoblast cells: false-positive results in 11 out of 51 cases[J].Eur J Obstet Gynecol Reprod Biol. 2002 ,101(2):161-168.
[169]Tongsong T, Sirichotiyakul S, Wanapirak C, Chanprapaph P Sonographic features of trisomy 13 at midpregnancy[J]. Int J Gynaecol Obstet. 2002 ,76(2):143-148.
[170]Epps RE,Pittelkow MR,Su WP.TORCH syndrome[J].Semin Dermatol,1995 14(2):179-186.
[171]Tolfvenstam T,Papadogiannakis N,Norbeck O,et al.Frequency of human parvovirus B19 infection in intrauterine fetal death[J].Lancet, 2001,357(9267): 494-1497.
[172]Botto LD,Correa A.Decreasing the burden of congenital heart anomalies: an epidemiologic evaluation of risk factors and survival [J].Prog Pediat Cardiol,2003,18(1):111-121.
[173]Scialli AR.Identifying teratogens: the tyranny of lists[J].Reprod Toxicol,..1997, 11(4):555-559.
[174]Edilberto Martinez,Sian AT,et al.Fetal cardiac implication of maternal systemic diseases[J]. Progress in Pediatric cardiology,1996,5: 91-101.
[175]Martinez E,Sian A-T,Kleinman CS,Copel JA,et al.Cardio implication of maternal systemic disease[J].Prog Pediat Cardiol,1996,5(1):91-101.
[176]Schulthesis TM, Xydas S, Lassar AB. Induction of avian cardiac myogenesis byanterior endoderm[J]. Development, 1995,121:4203–4214
[177]Galli D,Dominguez JN,Zaffran S,et al.Atrial myocardium derives from the posterior region of the second heart field,which acquires left-right identity as Pitx2c is expressed [J].Development,3008,135(6):1157-1167
[178]Tessari A,Pietrobon M,Notte A,et al.Myocardial Pitx2 differentially regulates the left atrial identity and ventricular asymmetric remodeling programs [J].Cric Res, 2008, 102(7):813-822
[179]Nouira S,Kamoun I,Ouragini H,et al.Clinnical and genetic investigation of atrial septal defect with atrioventricular conduction defect in a large consanguineous Tunisian family[J].Arch Med Res,2008,39(4):429-433
[180]Srivastava D . Genetic assembly of the heart: implications for congenital heart disease [J]. Annu. Rev. Physiol, 2001, 63:451-469.
[181]Joziasse IC,van de Smagt JJ,Smith K,et al.Genes in congenital heart disease:atrioventricular valve formation [J].Basic Res Cardiol, 2008, 103(3):216-227
[182]Zhu Y,Gramolini AO,Walsh MA,et al.Tbx5-dependent pathway regulating diastolic function in congenital heart disease[J].Proc Natl Acad Sci USA,2008,105(14): 5519-5524
[183]Qu X,Jia H,Garrity DM,et al.Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish[J].Dev Biol,2008,317(2):486-496
[2]Costa RH. Hepatocyte nuclear factor 3/forkhead protein family: mammalian transcription factors that pocess divergent cellular expression patterns and binding specificities [M]. In Tronche F, and Yaniv M(eds.), Liver Gene Expression, R.G.Landes company, Austin, TX. 1994.
[3]Kaufmann E, Kn?chel W. Five years on the wings of fork head [J]. Mech Dev, 1996, 57: 3–20.
[4]Katoh M.Human FOX gene family[J].Int J Oncol,2004,25(5):1495-1500.
[5]Susan LD, Rebecca LH, Robert PE, et al. Glover FOXC2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome[J]. Gene Expression Patterns, 2004, 4: 611-619.
[6]Miura N, Iida K, Kakinuma H, et al. Isolation of the mouse (MFH-1) and human (FKHL-14) mesenchyme fork head–1 gene reveals conservation of their gene and protein structures [J]. Genomics,1997, 41(3):489-492.
[7]Kaestner KH, Bleckmann SC, Monaghan AP, et al. Clustered arrangement of winged helix genes fkh-6and MFH-1:possible implications for mesoderm development [J].Development, 1996, 122(6):1751-1758.
[8]Wilm B,James RG,Schultheiss TM,Hogan BL.The forkhead genes,Foxc1 and Foxc2,regulate paraxial versus intermediate mesoderm cell fate[J].Dev Biol,2004, 271(1):176-189.
[9]Miura N, Wanaka A, Tohyama M, et al. MFH-1, a new member of the fork head domain family is expressed in developing mesenchyme[J]. FEBS Lett,1993,326(1-3): 171-176.
[10]Baldwin AL,Ferrer P,Rozum JS,et al.Regulation of water balance between blood and lymph in the frog,Ranapipiens[J].Lymphology, 1993, 26(1):4-18.
[11]Qiao R,Wang H,YanWL,et al.Hyaluronan in extracellularmatrix is a determinant ofendothelial barrier[J].Am J Physiol,1995,269:110-117.
[12]Makinen T,Norrmen C,Petrova TV.Molecular mechanisms of lymphatic vascular development[J].Cell Mol Life Sci,2007,64(15):1915-1929
[13]王炜.整形外科学[M].浙江:科学技术出版社.1999,1534-1542.
[14]Tammela T,Petrova TV,Alitalo K.Molecular lymphangiogenesis:new players[J]. Trends Cell Biol,2005,15(8):434-441.
[15]Ferrell RE,Kimak MA,Lawrence EC,et al.Candidate gene analysis in primary lymphedema[J].Lymphat Res Biol,2008,6(2):69-76.
[16]Wu X,Liu NF.FOXC2 transcription factor:a novel regulator of lymphangio- genesis[J].Lymphology,2011,44(1):35-41.
[17]Dagenais SL,Haitsough RL,Erickson RP,et al.Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndro- me[J].Gnen Expr Patterns,2004,4(6): 611-619.
[18]Gombos Z, Xu X, Chu CS, Zhang PJ, Acs G. Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix [J].Clin Cancer Res 2005;11(23):8364-8371.
[19]Mellor RH,Tate N,Stanton AW,et al.Mutations in FOXC2 in human lymphedema distichiasis syndrome) [J].J Vase Res,2011,48(5):397-407.
[20]Petrova TV, Karpanen T, Norrme′n C, Mellor R, Tamakoshi T, Finegold D, et al.Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis [J]. Nat Med 2004;10(9):974-981.
[21]Shimoda H, Bernas MJ, Witte MH. Dysmorphogenesis of lymph nodes in Foxc2 haploinsufficient mice[J]. Histochem Cell Biol. 2011 Jun;135(6): 603-13.
[22]田丽娜,邓伟国,邹积艳,马莉,丁言良,宋文龄,付艳.叉头框C2在人胚淋巴管发生过程中的表达[J].解剖学报,2008,39(6):886-889.
[23]Fang J, Dagenais SL, Erickson RP, et al. Mutations in FOXC2(MFH21),a forkhead family transcription factor, are responsible forthe hereditary lymphedema-distichiasis syndrome[J].An J Hum Genet, 2000,67(6):1382 -1388.
[24]Yabuki S,Kikuchi S,Ikegewa S.Spinal extradural arachniod cysts associated withdiatichiasis and lymphedema[J].Am J Med Genet A,2007,143 (8):884-887.
[25]Mansour S, Brice GW, Jeffery S, Mortimer P. Lymphedema-Distichiasis Syndrome. [J].Gene Reviews,2007,8(2):1993-2005.
[26]Raboulsi EI,Al-Khayer K,Matsumoto M,et al.Lymphedema-distichiasis syndrome and FOXC2 gene mutation [J]. Am J Ophthalmol, 2002, 134(4): 592-624.
[27]Retrova TV,Karpanen T,Norrmen C,et al.Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis[J]. Nat Med,2004,10(9):974-981.
[28]Brice G, Mansour S, Bell R, et al. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24 [J]. J Med Genet, 2002, 39(7): 478-483.
[29]Erickson R P, Dagenais S L, CaulderM S, et al. Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutation [J]. J Med Genet, 2001,38(11):761-766.
[30]Bell R,Brice G,Child A H,et al.Analysis of lymphoedema-distichiasis families for FOXC2 mutations reveals small insertions and deletions throughtout the gene[J]. Hum Genet, 2001,108(6):546-551.
[31]Berry FB,Tamimi Y,Carle MV,et al. The establishment of a predictivemutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis[J]. Hum Mol Genet, 2005,14 (18):2619-2627.
[32]ELIAS I, TRABOULSI, KHOULOUD AL-KHAYER, MASAYUKI MATSUMOTO, et al. Lymphedema–Distichiasis Syndrome and FOXC2 Gene Mutation[J]. AMERICAN JOURNAL OF PHTHALMOLOGY.2002,134(4):592-596.
[33]Arash Ghalamkarpour,Christian Debauche,Eric Haan, BMedSc, et al. Sporadic In Utero Generalized Edema Caused by Mutations in the Lymphangiogenic Genes VEGFR3 and FOXC2[J]. THE JOURNAL OF PEDIATRICS. 2009,155(1):90-93.
[34]Fauret AL, Tuleja E, Jeunemaitre X, Vignes S. A novel missense mutation and two microrearrangements in the FOXC2 gene of three families with lymphedema-distichiasissyndrome[J]. Lymphology. 2010 Mar;43(1): 14-18.
[35]Robert P Erickson,Susan L Dagenais,Mark S Caulder, et al.Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations[J].J Med Genet,2001:38: 761-766
[36]David N,Finegold,Mark A Kimak, et al.Truncating mutations in FOXC2 cause muitiple lymphedema syndromes[J].Human Molecular Genetics,2001, 10(11):1185-1189.
[37]Fauret AL,Tuleja E,Jeunemaitre X,et al.A novel missense mutation and two microrearrangements in the FOXC2 gene of three families with lymphedema- distichiasis syndrome[J].Lymphology,2010,43(1):14-18.
[38]Fabretto A,Shardlow A,Faletra F,et al.A case of lymphedema- distichiasis syndrome carrying a new de novo frameshift FOXC2 mutation[J].Ophthalmic Genet,2010, 31(2):98-100.
[39]Rriederman BM, Myloyde TL, Witte MH, et al. FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome [J]. Hum Mol Genet, 2003, 12(10): 1179-1185.
[40]Agenais SL, Hartsough RL, Erickson RP, et al. Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema–distichiasis syndrome [J]. Gene Expression Patterns, 2004, 4(6): 611-619.
[41]Mellor RH, Tate N, Stanton AW, Hubert C, M?kinen T, Smith A, Burnand KG, Jeffery S, Levick JR, Mortimer PS. Mutations in FOXC2 in humans (lymphoedema distichiasis syndrome) cause lymphatic dysfunction on dependency. [J]. J Vasc Res. 2011;48(5):397-407.
[42]Kriederman BM, Myloyde TL,Witte MH,et al.FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome [J].Hum Mol Genet, 2003, 12 (10):1179-85.
[43]Mellor RH, Brice G, Stanton A.WB, et al. Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb [J]. Journal of Vascular Surgery 2007,:608-612
[44]Russell H. Mellor, Glen Brice, Anthony W.B. Stanton, Jane French, , et al.Mutations inFOXC2 Are Strongly Associated With Primary Valve Failure in Veins of the Lower Limb [J]. Circulation 2007;115:1912-20.
[45]Wu X, Liu NF. FOXC2 transcription factor: a novel regulator of lymphangio- genesis [J].Lymphology.2011 Mar;44(1):35-41.
[46]Bruyn G, Casaer A, Devolder K, Van Acker G, Logghe H, Devriendt K, Cornette L. Hydrops fetalis and pulmonary lymphangiectasia due to FOXC2 mutation: anautosomal dominant hereditary lymphedema syndrome with variable expression[J]. Eur J Pediatr. 2011,Sep,15, [Epub ahead of print].
[47]Kume T, Jiang H, Topczewska JM, et al. The murine winged helix transcription factors, Foxc1 and FOXC2, are both required for cardiovascular development and somitogenesis [J]. Genes Dev, 2001,15(18): 2470-2482.
[48]Dang J M,Dagenais S L,Erickson R P,et al. Mutations in Foxc2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet, 2000,67(6):1382-1388.
[49]付艳,邓伟国,李玉林等.叉头框c2在中轴骨骼发育过程中的作用.中国病理生理杂志[J].2004,20(11):1966-1971.
[50]Wotton KR, Shimeld SM. Analysis of lamprey clustered Fox genes: Insight into Fox gene evolution and expression in vertebrates[J]. Gene. 2011 Aug 31,[Epub ahead of print].
[51]刘珉,刘伟.FOXC2的研究进展[J].上海第二医科大学学报, 2005,7:757 -760.
[52]Park SJ, Gadi J, Cho KW, Kim KJ, Kim SH, Jung HS, Lim SK.The forkhead transcription factor Foxc2 promotes osteoblastogenesis via up-regulation of integrinβ1 expression[J]. Bone. 2011 Sep;49(3):428-38.
[53]Kriederman BM, Myloyde TL, Witte MH, Dagenais SL, Witte CL, Rennels M,Bernas MJ,et al.FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome. Hum Mol Genet, 2003,12 (10):1179 -1185.
[54]Timur AA,Driscoll DJ,Wang Q.Biomedicine and diseases:the Klippel- Trenaunay syndrome,vascular anomalies and vascular morphogenesis[J].Cell Mol Life Sci,2005, 62(13):1434-1447.
[55]Lamont RE,Childs S.MAPping out arteries ang veins[J].Sci STKE,2006, 2006 (355):39-45.
[56]Ng MY,Andrew T,Spector TD,et al.Lingage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy,unselected sibling pairs[J].J Med Genet,2005, 42(3):235-239
[57]Bahuau M,Houdayer C,Tredano M,et al.FOXC2 truncating mutation in distichiasis, lymphedema, and cleft palate [J].Clin Genet., 2002, 62(6): 470-473.
[58]Brooks BP,Dagenais SL,Nelson CC,et al.Mutation of the FOXC2 gene in familial distichiasis [J].J AAPOS, 2003, 7(5):354-357.
[59]Kanzaki-Kato N,Tamakoshi T,Fu Y,et al.Poles of forkhead transcri- ption factor Foxc2(MFH-1) and endothelin receptor A in cardiovascular morphogenesis[J]. Cardiovasc Res,2005,65(3):711-718.
[60]Li D,Yan D,Liu W,et al.Foxc2 overexpression enhances benefit of endothelial progenitor cells for inhibiting neointimal formation by promoting CXCR4-dependent homing[J].J Vasc Surg,2011,53(6):1668-1678.
[61]Yu S,Shao L,Kilbride H,et al.Haploinsufficiencies of FOXC1and FOXC2 genes associated with lethal alveolar capillary dysplasia and congenital heart disease[J].Am J Med Genet A,2010,152A(5):1257-1262.
[62]Ramsey A. Saleem, Sharmila Banerjee-Basu, Fred B. Berry, et al. Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1. Human Molecular Genetics, 2003,22;2993-3005.
[63]Seo S,Fujita H,Nakano A.The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development [J].Dev Biol,2006,294(2):458-470.
[64]Seo S,Kume T.Forkhead transcription factors,Foxc1 and Foxc2,are required for the morphogenesis of the cardiac outflow tract[J].Dev Biol,2006,296(2):421-436.
[65]Kume T,Deng K,Hogen BL.Murine forkhead/winged helix genes Foxc1(Mf1) and Foxc2(Mf2) are required for the early organogenesis of the kidney and urinary tract[J].Development,2000,127(7):1387-1395.
[66]Takemoto M,He L,Norlin J,et al.Large-scale identification of genes implicated in kidney glomerulus development and function[J].EMBO J, 2006,25(5):1160-1174.
[67]White JT,Zhang B,Cerqueira DM,et al.Notch signaling,wt1 and foxc2 are key regulators of podocyte gene regulatory network in Xenopus[J]. Development,2010, 137(11) 1863-1873.
[68]Mitchell EK,Taylor DF,Woods K,et al.Differential gene expression in the developing mouse ureter[J].Gene Expr Patterns, 2006,6(5):519-538.
[69]Bergman RN, Van Citters GW, Mittelman SD, et al. Central role of the adipocyte in the metabolic syndrome[J]. J Investig Med, 2001, 49(1): 119-126.
[70]Morrison RF, Farmer SR. Hormonal signaling and transcriptional control of adipocyte differentiation [J]. J Nutr, 2000, 130(12): 3116S-3121S.
[71]Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ [J]. Proc Nutr Soc, 2001,60(3): 329-339.
[72]Rajala MW, Scherer PE. Minireview: The adipocyte--at the crossroads of energy homeostasis, inflammation, and atherosclerosis[J]. Endocrinology, 2003, 144(9): 3765-3773.
[73]Prins JB and O'Rahilly S. Regulation of adipose cell number in man [J]. Clin Sci (Lond), 1997, 92(1): 3-11.
[74]Tong Q, Dalgin G, Xu H, et al. Function of GATA transcription factors in preadipocyte-adipocyte transition [J]. Science, 2000, 290(5489):134 -138.
[75]Moldes M, Zuo Y, Morrison RF, et al. Peroxisome-proliferators -activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis [J]. Biochem J, 2003, 376(Pt 3): 607-613.
[76]Davis KE, Moldes M, Farmer SR. The forkhead transcription factor FoxC2 inhibits white adipocyte differentiation [J]. J Biol Chem, 2004,279(41): 42453-42461.
[77]Isabelle Gerin,Guido T.Bommer,Martin E.Lidell,et al.On the Role of FOX Transcription Factors in Adipocyte Differentiation and Insulin- stimulated Glucose Uptake[J].J Biol Chem,2009,284(16):10755–10763.
[78]Krings A,Rahman S,Huang S,et al.Bone marrow fat has brown adipose tissuecharacteristics,which are attenuated with aging and diabetes[J]. Bone,2011,Jun,24,[Epub ahead of print].
[79]Davis KE,Moldes M,Farmer SR.The forkhead transcription factor Foxc2 inhibits white adipocyte differentiation[J].J Biol Chem,2004,279(41): 42453-42461.
[80]Jason K. Kim,Hyo-Jeong Kim,So-Young;Park,et al. Adipocyte-Specific Overexpression of FOXC2 Prevents Diet-Induced Increases in Intramuscular Fatty Acyl CoA and Insulin Resistance[J].Diabetes,2005,54:1657-1663.
[81]Shaat N,Lernmark A,Karlsson E,et al.A variant in the transcription factor 7-like 2(TCF7L2) gene is associated with an increase risk of gestational diabetes mellitus [J].Diabetologia,2007,50(5):972-979.
[82]Komulainen,Kati;Peltonen,et al.The Effect of Variants of Familial Combined Hyperlipidemia Candidate Genes, USFL and FOXC2, on Cardiova- scular Atherosclerotic Lesions[J].Circulation,2005,46(4):187-194.
[83]Lidell ME,Seifert EL,Westergren R,et al.The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function[J].Diabetes, 2011,60(2):427-435.
[84]Kovacs P, Lehn-Stefan A, Stumvoll M, et al. Genetic variation in the human winged helix/forkhead transcription factor gene FOXC2 in Pima Indians. Diabetes,2003,52: 1292-1295.
[85]Yanagisawa K, Hingstrup Larsen L, Andersen C, et al. The FOXC2 -512C>Tvariant is associated with hypertriglyceridaemia and increased serum C-peptide in Danish Caucasian glucose-tolerant subjects.Diabetologia, 2003, 46 :1576-1580.
[86]Xue Y,Cao R,Nilsson D,Chen S,Westergren R,Hedlund EM,Martijn C, Rondahl L,Krauli P,Walum E,Enerb?ck S,Cao Y.FOXC2 controls Ang-2 expression and modulates angiogenesis, vascular patterning, remodeling, and functions in adipose tissue[J].Proc Natl Acad Sci U S A,2008,105 (29):10167–10172.
[87]Huber, M. A., Kraut, N., & Beug, H.. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Current Opinion in Cell Biology, 2005, 17:1–11.
[88]Hader C,Marlier A,Cantley L.Mesenchymal-epithelial transition in epithelial response to injury:the role of Foxc2[J].Oncogene,2010,29(7): 1031-1040.
[89]Mani SA,Yang J,Brooks M,et al.Mesenchyme forkhead 1(FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers[J].Proc Nat1 Acad Sci USA,2007,104(24):10069-10074.
[90]Nishida N,Mimori K,Yokobori T,et al.FOXC2 is a novel prognostic factor in human esophageal squamous cell carcinoma[J].Ann Surg Oncol, 2011,18(2):535-542.
[91]Saxena M,Stephens MA,Pathak H,et al.Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters[J].Cell Death Dis,2011,2(6):179-184.
[92]Sano H,Leboeuf JP,Novitskiy SV,et al.The Foxc2 transcription factor regulates tumor angiogenesis[J].Biochem Biophys Res Commun,2010,392(2): 201-206
[93]Gould DB,Smith RS,John SW.Anterior segment development relevant to glaucoma [J].Int Dev Biol,2004,48(8-9):1015-1029.
[94]王彦,于青.山东省出生缺陷发生率与婚检率的关系[J].泰山医学院学报,2010,31(10):779-780.
[95]马二铃,张敬如,张国华,陈景伟,张彦玲.石家庄地区2005至2009年城乡围产儿出生缺陷临床分析[J].河北医药,2010,32(24):3558-3559.
[96]曾萼.广西壮族自治区以人群为基础的出生缺陷监测结果分析[J].中国妇幼保健,2010,25(25):3587-3588.
[97]刘凯波,潘迎,丁辉.2006年北京市出生缺陷监测数据分析[J].中国优生与遗传杂志,2007,15(6):95-97.
[98]Hansen M,Sullivan E,Jequier AM,Burton P,Junk S,Yovich J,Bower C. Practitioner reporting of birth defects in children born following assisted reproductive technology: Does it still have a role in surveillance of birth defects? Human[J].Reproduction, 2007,22(2): 516– 520.
[99]Shaer C M,Chescheir N,Schulkin J.Myelomeningocele: A Review of the Epidemiology, Genetics, Risk Factors for Conception, Prenatal Diagnosis, and Prognosis for Affected Individuals[J].Obstet &Gynecol Survey,2007, 62(7):471-479.
[100]Evans M I,Llurba E,Landsberger EJ,O’Brien J E,Harrison H H.Impact of Folic Acid Fortification in the United States: Markedly Diminished High Maternal Serum Alpha-Fetoprotein Values[J].Obstet &Gynecol.2004,103(3): 474-479.
[101]Ford N,Calmy A,Mofensen L.Safety of efavirenz in first-trimester of pregnancy: an updated systematic review and meta-analysis[J].AIDS,2011, 00(00):1-4.
[102]乐杰.妇产科学[M].第7版.北京:人民卫生出版社,2008,132.
[103]Stauffer NR,Murphy K.Prenatal diagnosis of congenital heart disease: the beginning[J].Crit Care Nurs Q,2002,25(3):1-7.
[104]Allan LD.Fetal cardic anomalies[J]. Prog Pediatr Cardiol,1996(5): 103-112.
[105]卢媛,李莹,刘婷婷.武昌地区13家助产机构2006至2009年围生儿出生缺陷分析[J].中华妇幼临床医学杂志(电子版),2011,7(2):133-136.
[106]蒲柳艳,吴金华.浙江省舟山市定海区出生缺陷监测与父母相关因素研究[J].疾病监测,2010,25(10):806-892.
[107]崔慧芳.17188例围产儿出生缺陷监测分析及干预措施探讨[J].中国优生与遗传杂志,2010,18(6):110-111.
[108]胡继宏,赵燚,刘兰,吴海鹰,张涛,宋晨阳.宁夏回族自治区0~1岁婴儿出生缺陷发生率普查情况分析[J].中国计划生育学杂志,2010,2:92-94.
[109]Cabrera RM,Hill DS,Etheredge AJ,et al. Investiations into the etiology of neural tube defects [J]. Birth Defects Res C Embryo Today, 2004,72(4):330-344.
[110]代礼,朱军,周光萱,等.1996～2000年全国神经管缺陷的动态监测[J].中华预防医学杂志. 2002,36(6):402-405.
[111]Ford N,Calmy A,Mofensen L.Safety of efavirenz in first-trimester of pregnancy: an updated systematic review and meta-analysis[J].AIDS, 2011, Sep,13,[Epub ahead of print].
[112]Bruneau BG.Mouse model of cardia chamber formation and congenital heart disease[J]. Trends in Genetics,2002,18,(6):15-20.
[113]胡昕婴,史剑慧,葛均波.心肌分化的调控[J].国外医学遗传学分册,2003,26:209-212.
[114]Brown CO,Chi X,Garcia-Gas E,et al.The cardiac determination factor, Nkx2-5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer[J].Jboil Chem,2004,279(11):10659-10669.
[115]Lin CR,Kioussi C,O'Connell S,Briata P,Szeto D,Liu F,Izpisúa-Belmonte JC, Rosenfeld MG.Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis[J].Nature,1999, 401(6750):279-282.
[116]Srivastava D,Thomas T,Lin Q,Kirby ML,Brown D,Olson EN.Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND[J].Nat Genet,1997,16(2):154-160.
[117]Grewal J,Carmichael SL,Ma C,Lammer EJ,Shaw GM.Maternal periconcep- tional smoking and alcohol consumption and risk for select congenital anomalies[J]. Birth Defects Res A Clin Mol Teratol,2008,82(7):519-526.
[118]Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H, Gravel RA, Rozen R. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida[J].Mol Genet Metab,1999,67(4):317-23.
[119]Vieira AR, Meira R, Modesto A,et al. MSX1, PAX9, and TGFA contribute to tooth agenesis in humans[J].J Dent Res, 2004,83(9):723- 727.
[120]Kume T.Foxc2 transcription factor: a newly described regulator of angiogenesis[J]. Trends Cardiovasc Med,2008,18(6):224-228.
[121]Bard JB,Lam MS,Aitken S.Bioinformatics approach for identifying candidate transcriptional regulators of mesenchyme-to-epithelium transitions in mouse embryos [J].Dev Dyn,2008,237(10):2748-2754.
[122]上海第一医学院.组织胚胎学[M].北京:人民卫生出版社,1978,373-376.
[123]刘斌,高英茂.人体胚胎学[M].北京:人民卫生出版杜,1996, 366-371.
[124]Kaestner KH,Bleckmann SC,Monaghan AP,Schl?ndorff J, Mincheva A, Lichter P and Schütz G. Clustered arrangement of winged helix genes fkh-6and MFH-1: possible implications for mesoderm development[J]. Development,1996,122: 1751-1758.
[125]Kirby ML,Waldo KL.Neural crest and cardiovascular patterning [J].Circ Res, 1995,77(2):211-215.
[126]Le Lievre CS,Le Douarin NM.Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos[J].J Embryol Exp Morphol,1975,34(1):125-154.
[127]Larsen WJ.人类胚胎学Human Embryology(英文版)[M].北京:人民卫生出版社-Health Science Asia Elsevier Science,2002:196-222.
[128]Mitchell EK,Taylor DF,Woods K,Davis MJ,Nelson AL,Teasdale RD,Grimmond SM,Little MH,Bertram JF,Caruana G.Differential gene expression in the developing mouse ureter[J].Gene Expr Patterns,2006, 6(5):519-538.
[129]Finegold DN,Kimak MA,Lawrence EC,Levinson KL,Cherniske EM,Pober BR, Dunlap JW,Ferrell RE.Truncating mutations in FOXC2 cause multiple lymphedema syndromes [J].Hum Mol Genet,2001,10(11):1185-1189.
[130]Smith RS,Zabaleta A,Kume T,Savinova OV,Kidson SH,Martin JE, Nishi- mura DY,Alward WL,Hogan BL,John SW.Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development[J].Hum Mol Genet,2000,9 (7):1021-1032.
[131]Melve KK, Skj?rven R. Families with birth defects: is birth weight of nonmalformed siblings affected? [J].Am J Epidemiol,2002,155:932–940.
[132]Lie RT, Wilcox AJ, Skj?rven R. Survival and reproduction among males with birth defects and risk of recurrence in their children [J].JAMA, 2001,285:755–760.
[133]Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A,Taylor DJ.Childhood Outcomes After Prescription of Antibiotics to Pregnant Women With Spontaneous Preterm Labour: 7-Year Follow-Up of the ORACLE II Trial [J].Lancet 2008;372: 1319–1327.
[134]付丽杰,阎云,张红恩.畸胎学[M].上海:上海科技教育出版社,1996,18- 157.
[135]Brown CO,Chi X,Garcia-Gas E,et al.The cardiac determination factor, Nkx2-5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer [J].J boil Chem,2004,279(11):10659-10669.
[136]谌琛,惠汝太.心脏特异转录因子及其对心脏发育和心脏基因的调控[J].中国分子心脏病学杂志,2005,5(3):561-565.
[137]Shiratori H,Yashiro K,Shen MM,Hamada H.Conserved regulation and role of Pitx2 in situs-specific morphogenesis ofvisceral organs[J]. Development,2006,133(15):3015-25.
[138]Lin CR,Kioussi C,OConnell S,et al.Pitx2 regulates lung asymmetry, cardiacpositioning and pituitary and tooth morphogenesis[J].Nature, 1999,401:279-282.
[139]Van Tuyl M,Liu J,Groenman F,et al.Iroquois genes influence proximo-distal morphogenesis during rat lungdevelopment[J].Am J Physiol Lung Cell Mol Physiol,2006,290(4):L777-L789.
[140]Hiroyuki Yamagishi,Eric N.Olson, Deepak Srivastava.The basic helix-loop-helix transcription factor, dHAND, is required for vascular development[J].The Jounal of Clinical Investigation, 2000,105:261-270.
[141]Tevosian S, Deconinck A, Tanaka M, et al.FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and Development of coronary vessels from epicardium[J].Cell,2000,101: 729-39.
[142]Ota K G,Fujimoto S,Oisi Y,Kuratani S.Identification of vertebra-like elements and their possible differentiation from sclerotomes in the hagfish[J].Nat Commun,2011, 28(2):373-378.
[143]Kume T, Jiang H, Topczewska JM, et al.The murine winged helix transcription factors, Foxc1 and FOXC2, are both required for cardiovascular development and somitog- enesis [J]. Genes Dev, 2001, 15(18):2470-2482.
[144]Sholto-Douglas-Vernon C, Bell R, Brice G, et al. Lymphoedema- distichiasi and FOXC2:unreported mutations, de novo mutation estimate, families without coding mutation[J].2005, 117: 238-242.
[145]罗美瑜.我国出生缺陷的现状及干预[J].海峡预防医学杂志,2006,12(5): 1-2.
[146]任太芳,素芳.新乡地区10506例围产儿中先天畸形及有关致畸因素的分析[J].中国优生与遗传杂志, 2005,13(1):100-113.
[147]胡荣华,杜玉开.武汉市围产儿先天畸形流行状况及影响因素研究[J].医学与社会, 2005,18(1):7-11.
[148]李颖,杨柳,杨文方.出生缺陷的相关因素[J].中国计划生育学杂志,2010,12(183): 755-757.
[149]白亚娜,屈燕,胡晓斌.出生缺陷致病因素的多因素分析[J].中国妇幼保健, 2004,19(5):44-46.
[150]ICBDMS1 Quarterly report of International Clearinghouse for Birth Defects Monitoring [J]. Systems, 3rd quarter July-August 2000. Roma Icbdms,2001.2-5.
[151]常利利.323例新生儿先天畸形相关因素的临床研究.吉林大学硕士学位论文,2008年.
[152]王玮,许伟,郑亚军,周宝森.先天畸形危险因素的病例对照研究[J].中国儿童保健杂,2007,15(4):403-405.
[153]Wotton KR,Shimeld SM.Analysis of lamprey clustered Fox genes: Insight into Fox gene evolution and expression in vertebrates[J]. Gene,2011,489(1):30-40.
[154]Park SJ,Gadi J,Cho KW,Kim KJ,Kim SH,Jung HS,Lim SK.The forkhead transcription factor Foxc2 promotes osteoblast ogenesis via up-regulation of integrinβ1 expression[J].Bone,2011,49(3):428-438.
[155]Mellor,Russell H,Brice,Glen,Stanton,,Anthony W B,et al.Mutations in FOXC2 Are Strongly Associated With Primary Valve Failure in Veins of the Lower Limb[J]. Circulation,2007,115:1912-1920.
[156]付艳,邓伟国,李艺扬等.叉头框-C2基因在主动脉弓发育过程中的作用[J].生物化学与生物物理进展,2003,30(5):726-731.
[157]De Bruyn G,Casaer A,Devolder K,Van Acker G,Logghe H,Devriendt K,Cornette L.Hydrops fetalis and pulmonary lymphangiectasia due to FOXC2 mutation: an autosomal dominant hereditary lymphedema syndrome with variable expression[J].Eur J Pediatr,2011,Sep 15,[Epub ahead of print].
[158]Stauffer NR,Murphy K.Prenatal.diagnosis f congenital heart disease: the beginning [J].Crit Care Nurs Q,2002,25(3):1-7.
[159]Allan LD.Fetal cardic anomalies[J].Prog Pediatr Cardiol,1996(5): 103-112.
[160]庄依亮.妊娠合并先天性心血管疾病.曹泽毅.中华妇产科学[M].北京:人民卫生出版社,1999,452-465.
[161]Marino B,Digilio MC.Congenital Heart Disease and Genetic Syndromes: Specific Correlation Between Cardic Phenotype and Genotype[J]. Cardiovasc Pathol,2000,9(6): 303-315.
[162]田中誠 ,北徹.心臓の発生と先天性心疾患のメカニズム[J].実験医学,2000,18(16):2280-2285.
[163]McFadden DG, Charite J, Richardson JA, et al. A GATA-dependent right ventricular enhancer controls dHAND transcription in the developing heart[J]. Development. 2000,127(24):5331-5341.
[164]Liu ZP, Nakagawa O, Nakagawa M, et al CHAMP, a novel cardiac-specific helicase regulated by MEF2C[J].Dev Biol. 2001,234(2):497-509.
[165]Lo CW, Wessels A.Cx43 Gap Junctions in Cardiac Development[J]. TCM, 1998, 9(6):264-269
[166]Junker R, Kotthoff S, Vielhaber H, Halimeh S, Kosch A, Koch HG, Kassenbohmer R, Heineking B, Nowak-Gottl U. Infant methylenetetrahydro- folate reductase 677TT genotype is a risk factor for congenital heart disease[J]. Cardiovasc Res. 2001,51(2):251-254.
[167]Lindsay EA, Baldini A. Congenital heart defects and 22q11 deletions: which genes count[J]? Mol Med Today. 1998,4(8):350-357.
[168]Schuring-Blom GH, Boer K, Knegt AC, et al. Trisomy 13 or 18 (mosaicism) in first trimester cytotrophoblast cells: false-positive results in 11 out of 51 cases[J].Eur J Obstet Gynecol Reprod Biol. 2002 ,101(2):161-168.
[169]Tongsong T, Sirichotiyakul S, Wanapirak C, Chanprapaph P Sonographic features of trisomy 13 at midpregnancy[J]. Int J Gynaecol Obstet. 2002 ,76(2):143-148.
[170]Epps RE,Pittelkow MR,Su WP.TORCH syndrome[J].Semin Dermatol,1995 14(2):179-186.
[171]Tolfvenstam T,Papadogiannakis N,Norbeck O,et al.Frequency of human parvovirus B19 infection in intrauterine fetal death[J].Lancet, 2001,357(9267): 494-1497.
[172]Botto LD,Correa A.Decreasing the burden of congenital heart anomalies: an epidemiologic evaluation of risk factors and survival [J].Prog Pediat Cardiol,2003,18(1):111-121.
[173]Scialli AR.Identifying teratogens: the tyranny of lists[J].Reprod Toxicol,..1997, 11(4):555-559.
[174]Edilberto Martinez,Sian AT,et al.Fetal cardiac implication of maternal systemic diseases[J]. Progress in Pediatric cardiology,1996,5: 91-101.
[175]Martinez E,Sian A-T,Kleinman CS,Copel JA,et al.Cardio implication of maternal systemic disease[J].Prog Pediat Cardiol,1996,5(1):91-101.
[176]Schulthesis TM, Xydas S, Lassar AB. Induction of avian cardiac myogenesis byanterior endoderm[J]. Development, 1995,121:4203–4214
[177]Galli D,Dominguez JN,Zaffran S,et al.Atrial myocardium derives from the posterior region of the second heart field,which acquires left-right identity as Pitx2c is expressed [J].Development,3008,135(6):1157-1167
[178]Tessari A,Pietrobon M,Notte A,et al.Myocardial Pitx2 differentially regulates the left atrial identity and ventricular asymmetric remodeling programs [J].Cric Res, 2008, 102(7):813-822
[179]Nouira S,Kamoun I,Ouragini H,et al.Clinnical and genetic investigation of atrial septal defect with atrioventricular conduction defect in a large consanguineous Tunisian family[J].Arch Med Res,2008,39(4):429-433
[180]Srivastava D . Genetic assembly of the heart: implications for congenital heart disease [J]. Annu. Rev. Physiol, 2001, 63:451-469.
[181]Joziasse IC,van de Smagt JJ,Smith K,et al.Genes in congenital heart disease:atrioventricular valve formation [J].Basic Res Cardiol, 2008, 103(3):216-227
[182]Zhu Y,Gramolini AO,Walsh MA,et al.Tbx5-dependent pathway regulating diastolic function in congenital heart disease[J].Proc Natl Acad Sci USA,2008,105(14): 5519-5524
[183]Qu X,Jia H,Garrity DM,et al.Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish[J].Dev Biol,2008,317(2):486-496