单纯性马蹄内翻足与COL1A1基因的相关性研究
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摘要
前言
单纯性马蹄内翻足(idiopathic congenital talipes equinovar，ICTEV)是一种出生时即可见的复杂的先天性足畸形。在不同的人群中，ICTEV的发病率有很大差异，在我国约为0.6‰～1‰，男女之比约为2～2.5：1。近年来，国内外对于ICTEV的发病机制争论较多，但均缺乏有力的证据。临床资料和流行病学研究表明，遗传因素在ICTEV的发病过程中发挥重要的作用，但其遗传方式、外显率等均不清楚。目前认为ICTEV主要是在肢芽发育的易损期，由于遗传因素和环境因素的共同作用，某些与肢体发育有关的基因及其产物出现异常的结果。近年来，国内外对ICTEV致病基因的分子水平上的研究很少，研究多集中于对一些合并有类似足部畸形的综合征和多发畸形的研究。这些研究提供了ICTEV致病基因可能的侯选区域：5q15-31.1；6q12-13；7号染色体长臂；17号染色体长臂；10p11.2-15；9号染色体中心粒周围区等，通过生物信息学可知这些区域内存在着一些与骨骼、肌肉、肌腱、神经发育相关的基因，这为我们探寻ICTEV的易感基因提供了有利的线索。
目前的研究表明，在ICTEV患侧组织中存在纤维组织明显增加，其中Ⅰ型胶原增加最显著。Ⅰ型胶原是由两条α1链及一条α2链组成的三股螺旋结构。Ⅰ型胶原的α1链和α2链分别由COL1A1和COL1A2基因编码。COL1A1基因和COL1A2基因分别位于17q21.3-q22和7q21.3-q22。目前已发现上百种COL1A1基因突变，主要集中在外显子。COL1A1基因突变可导致多种疾病的发生，主要可引起先天性成骨不全、Ehlers Dahlos综合征(EDS)、骨质疏松症(Osteoporosis)。但是对于COL1A1基因与ICTEV相关性的进一步研究至今仍未见报道。本研究以COL1A1基因为候选基因，将从分子水平上进一步探讨Ⅰ型胶原基因与ICTEV发生的相关性。
为了从RNA水平上进一步观察ICTEV中的COL1A1基因表达水平的变化，本研究中我们首先构建了马蹄内翻足大鼠模型，并采用半定量RT-PCR的方法，对后肢发育不同时期的模型胎鼠和正常胎鼠后肢组织中Collal基因的表达水平进行了比较。接下来，我们又采用半定量RT-PCR方法，对20例ICTEV患儿和4例正常儿童的肌肉和肌腱组织中COLlAl基因的表达水平进行了比较。此外，为了探讨COLlAl基因表达水平变化的原因，我们选择了COLlAl基因转录起始点上游-1031bp～+30bp和第1内含子，对84例ICTEV患者进行了突变筛查。
材料与方法
一、研究对象：
Wistar大鼠86只，包括雌鼠65只和雄鼠21只，均购自校动物部。
肌肉及肌腱标本来自于20例手术矫正的ICTEV患儿，取4例外伤及尸检患儿相应组织作为正常对照，所有标本均经患者知情同意。
84例单纯性马蹄内翻足患者的静脉抗凝血，标本由中国医科大学第二临床医院小儿外科提供。其中男性60例，女性24例(男女之比为2.5：1)；年龄最大者28岁，最小者4个月；单侧马蹄内翻足者51例，双侧马蹄内翻足者33例(双侧者占39.28％)；所有患者均具有典型的临床症状，经X线和手术确诊。100例正常人DNA，研究对象均来自中国东北地区正常汉族人群。
二、实验方法
1、大鼠模型的构建及半定量RT-PCR检测模型鼠后肢Collal基因的表达
(1)构建大鼠模型通过在孕十天给孕鼠灌全反式维甲酸(135mg／kg体重)和矿物油分别获得马蹄内翻足模型胎鼠及正常对照胎鼠。
(2)观察Collal基因在动物模型中的表达情况分别取孕15天，17天，19天及21天的实验组和对照组胎鼠的后肢，常规提取总RNA并进行反转录得到cDNA，以β-actin为内对照采用半定量RT-PCR方法研究Collal基因在后肢发育不同阶段的表达情况。
2．半定量RT-PCR分析COLlAl基因在患儿及正常对照肌肉、肌腱组织中的表达
(1)按常规方法提取患儿及正常对照肌肉、肌腱组织中的总RNA，并进行反转录得到cDNA。
(2)以β-actin为内对照采用半定量RT-PCR方法研究COLlAl基因在患儿及正常对照肌肉、肌腱组织中的表达情况。
3．PCR-DGGE
(1) PCR扩增明确COLlAl基因上游转录调控区和第1内含子的基因序列，并应用Primer5软件设计引物(上海生工合成)，在上游引物的5′端加上40bp的[GC]夹。对84名单纯性马蹄内翻足患者DNA目的片段进行PCR扩增，并用1.5％的琼脂糖凝胶电泳检测。
(2) DGGE检测以变性剂浓度范围为20％—80％的聚丙烯酰胺凝胶做水平DGGE，并根据带形及其位置进一步调节变性剂浓度范围及电泳时间；电泳后，下胶，溴化乙锭染色，在紫外灯下观察结果。
(3)确定突变位点对电泳带形异常的PCR产物进行DNA测序以确定序列改变的位置与性质，并对正常人DNA的相同位点进行筛查，以判断该碱基置换是突变还是多态。
实验结果
一、模型胎鼠RT-PCR结果
RT-PCR结果显示在模型胎鼠后肢发育的各个时期均存在Collal基因表达的上调。
二、人COLlAl基因RT-PCR结果
ICTEV患儿肌肉及肌腱组织中COLlAl基因表达水平高于正常组织。
三、PCR-DGGE检测结果
经DGGE筛查并测序发现一名患者-161bp处存在C→T的杂合突变，另一名患者+274bp处存在C→G的纯合突变。分别经过对100名正常人的同一位点进行筛查，没有发现相同的改变，排除其为多态。经查找人类基因突变数据库(The Human Gene Mutation Database，HGMD)，证实是尚未见报道的新突变。
结论
1、应用半定量RT-PCR的方法发现在马蹄内翻足模型胎鼠后肢发育的不同时期均存在Collal基因表达的上调，同时发现单纯性马蹄内翻足患儿患侧肌肉及肌腱组织中COLlAl基因表达水平高于正常组织，证明了该基因与马蹄内翻足畸形的发生具有相关性。
2、在COLlAl基因-161bp处和+274bp处发现了新突变，提示该基因转录调控序列的突变可能是ICTEV的致病原因之一。
Objective
Idiopathic congenital talipes equinovarus (ICTEV) is a complex footdeformity presented at birth with 0.6‰～1‰birth rate in Chinese.The cause ofICTEV remains controversial. Many factors as skeleton development anomaly,neuromuscular disease,developmental arrest in uterus and so on seem to beresponsible. It is considered that the genetic factors play an important role in thepathogenesis of ICTEV, and the heritability of ICTEV is about 65%, it is yetunknown about the hereditary patterns and penetrance of ICTEV.Recently, it isbelieved that abnormal expression of some limb development-related genes leadsto ICTEV. At present,researches on human ICTEV mainly focus on manysyndromes with foot malformations,and little advances have been made in theresearches on the susceptibility genes of ICTEV. The researches provid somecandidate regions and genes for ICTEV such as 5q15-31.1,10p11.2-15 and soon,which provide an useful clue for us to look for the candidate genes of ICTEV.
Researches indicat that the content of typeⅠcollagen is remarkable increasedin ICTEV.TypeⅠcollagen is the most abundant and widly expressed collagen inhuman. It provides the structural support for the body in skeleton, skin, bloodvessele,nerves,intestines,and in the fibous capsules of organs. TypeⅠcollagen is aheterotrimer of two identicalαl(Ⅰ) chains and one chα2(Ⅰ) chain. Theαl(Ⅰ) andchα2(Ⅰ) chains of typeⅠcollagen are encoded by the unlinked loci COL1A1 andCOL1A2 respectively. COL1A1 and COL1A2 locate in 17q21.3-q22 and7q21.3-q22 respectively.Now, it has discovered hundred of mutations in COL1A1gene.Mutations at these loci result primarily in the connective tissue disorders: osteogenesis imperfecta,Ehler-Danlos syndrome typesⅦA andⅦB,Osteoporosis.But there is no report about association between COL1A1 andICTEV.In our study, we will probe into the association between COL1A1 andICTEV furtherly on molecular level.
In our studies,we constructed animal model of talipes equinovarus withWistar rats, and discovered that there was up-regulation of Collal gene expressionin different stage of limb development in the animal model by RT-PCR. Then,wealso discovered that there was up-regulation of COL1A1 gene expression in themusclar and tenden tissues of ICTEV patients by RT-PCR. At the sametime,mutation sites in transcription regular sequences(-1031bp～+30bp) and intron1 of COL1A1 gene were detected in 84 patients with ICTEV by denaturinggradient gel electrophoresis technique.The result was that we found a -161C→Theterozygous mutation and a +274C→G homozygous mutation in COL1A1gene.So,we thought COL1A1 gene was confirmed to be associated with ICTEV.
Material and Methods
1. Samples
86 Wistar rats were bought from the animal department of China MedicalUniversity.
Musclar and tenden tissues of 20 patients with ICTEV and correspondingnormal tissues came from the Second Affiliated Hospital, China MedicalUniversity.
84 patients with ICTEV came from the Second Affiliated Hospital, ChinaMedical University. All patients had typical manifestation and were confirmed byX-rays and surgical operation. 100 normal DNA come from normal crowd ofnortheastern china.
2.Construction of rat model and Study Collal gene in thehindlimbs of rat models with RT-PCR
135mg/kg body weight of ATRA was used to construct rat model on day 10 ofgestation, which has shown a good consistency with talipes equinovarusmalformation as that in humans. On day 15、17、19 and 21 of gestation,thehindlimbs were cut from model fetus and normal controls,and total RNA was extracted,then reverse transcribed to cDNA. RT-PCR was used to detecte theexpression of COL1A1.
3.Study COL1A1 gene in musclar and tenden tissues of ICTEVwith RT-PCR
The total RNA was extracted from musclar and tenden tissues of patients withICTEV and normal controls,then reverse transcribed to cDNA. RT-PCR was usedto detecte the expression of COL1A1.
4.PCR-DGGE
Mutation sites in transcription regular sequences(-1031bp～+30bp) andintron 1 of COL1A1 gene were detected in 84 patients with ICTEV by denaturinggradient gel electrophoresis technique.
Results
1.The expression of Collal gene in rat models
RT-PCR results found the expression of Collal gene up-regulated in differentstage of limb development in rat models with the clubfoot like deformity.
2. The expression of COL1A1 gene in muscles and tenden ofpatients with ICTEV
RT-PCR results found the expression of COL1A1 gene in musclar and tendentissues of ICTEV is higher than normal tissues.
3. Result of PCR-DGGE
The result was that we found a-161C→T heterozygous mutation and a+274C→G homozygous mutation in COL1A1 gene.
Conclusions
1.RT-PCR results found the expression of Collal gene up-regulated indifferent stage of limb development, and the expression of COL1A1 geneup-regulated in musclar and tenden tissues of patients with ICTEV,whichconfirmed the association between COL1A1 gene and talipes equinovarusdeformation.
2. We discovered a-161T→C heterozygous mutation and a +274C→Ghomozygous mutation in COL1A1 gene of patients with ICTEV. It illustrated that the mutation in transcription regular sequences could caused ICTEV.
单纯性马蹄内翻足(idiopathic congenital talipes equinovar，ICTEV)是一种出生时即可见的复杂的先天性足畸形。在不同的人群中，ICTEV的发病率有很大差异，在我国约为0.6‰～1‰，男女之比约为2～2.5：1。近年来，国内外对于ICTEV的发病机制争论较多，但均缺乏有力的证据。临床资料和流行病学研究表明，遗传因素在ICTEV的发病过程中发挥重要的作用，但其遗传方式、外显率等均不清楚。目前认为ICTEV主要是在肢芽发育的易损期，由于遗传因素和环境因素的共同作用，某些与肢体发育有关的基因及其产物出现异常的结果。近年来，国内外对ICTEV致病基因的分子水平上的研究很少，研究多集中于对一些合并有类似足部畸形的综合征和多发畸形的研究。这些研究提供了ICTEV致病基因可能的侯选区域：5q15-31.1；6q12-13；7号染色体长臂；17号染色体长臂；10p11.2-15；9号染色体中心粒周围区等，通过生物信息学可知这些区域内存在着一些与骨骼、肌肉、肌腱、神经发育相关的基因，这为我们探寻ICTEV的易感基因提供了有利的线索。
目前的研究表明，在ICTEV患侧组织中存在纤维组织明显增加，其中Ⅰ型胶原增加最显著。Ⅰ型胶原是由两条α1链及一条α2链组成的三股螺旋结构。Ⅰ型胶原的α1链和α2链分别由COL1A1和COL1A2基因编码。COL1A1基因和COL1A2基因分别位于17q21.3-q22和7q21.3-q22。目前已发现上百种COL1A1基因突变，主要集中在外显子。COL1A1基因突变可导致多种疾病的发生，主要可引起先天性成骨不全、Ehlers Dahlos综合征(EDS)、骨质疏松症(Osteoporosis)。但是对于COL1A1基因与ICTEV相关性的进一步研究至今仍未见报道。本研究以COL1A1基因为候选基因，将从分子水平上进一步探讨Ⅰ型胶原基因与ICTEV发生的相关性。
为了从RNA水平上进一步观察ICTEV中的COL1A1基因表达水平的变化，本研究中我们首先构建了马蹄内翻足大鼠模型，并采用半定量RT-PCR的方法，对后肢发育不同时期的模型胎鼠和正常胎鼠后肢组织中Collal基因的表达水平进行了比较。接下来，我们又采用半定量RT-PCR方法，对20例ICTEV患儿和4例正常儿童的肌肉和肌腱组织中COLlAl基因的表达水平进行了比较。此外，为了探讨COLlAl基因表达水平变化的原因，我们选择了COLlAl基因转录起始点上游-1031bp～+30bp和第1内含子，对84例ICTEV患者进行了突变筛查。
材料与方法
一、研究对象：
Wistar大鼠86只，包括雌鼠65只和雄鼠21只，均购自校动物部。
肌肉及肌腱标本来自于20例手术矫正的ICTEV患儿，取4例外伤及尸检患儿相应组织作为正常对照，所有标本均经患者知情同意。
84例单纯性马蹄内翻足患者的静脉抗凝血，标本由中国医科大学第二临床医院小儿外科提供。其中男性60例，女性24例(男女之比为2.5：1)；年龄最大者28岁，最小者4个月；单侧马蹄内翻足者51例，双侧马蹄内翻足者33例(双侧者占39.28％)；所有患者均具有典型的临床症状，经X线和手术确诊。100例正常人DNA，研究对象均来自中国东北地区正常汉族人群。
二、实验方法
1、大鼠模型的构建及半定量RT-PCR检测模型鼠后肢Collal基因的表达
(1)构建大鼠模型通过在孕十天给孕鼠灌全反式维甲酸(135mg／kg体重)和矿物油分别获得马蹄内翻足模型胎鼠及正常对照胎鼠。
(2)观察Collal基因在动物模型中的表达情况分别取孕15天，17天，19天及21天的实验组和对照组胎鼠的后肢，常规提取总RNA并进行反转录得到cDNA，以β-actin为内对照采用半定量RT-PCR方法研究Collal基因在后肢发育不同阶段的表达情况。
2．半定量RT-PCR分析COLlAl基因在患儿及正常对照肌肉、肌腱组织中的表达
(1)按常规方法提取患儿及正常对照肌肉、肌腱组织中的总RNA，并进行反转录得到cDNA。
(2)以β-actin为内对照采用半定量RT-PCR方法研究COLlAl基因在患儿及正常对照肌肉、肌腱组织中的表达情况。
3．PCR-DGGE
(1) PCR扩增明确COLlAl基因上游转录调控区和第1内含子的基因序列，并应用Primer5软件设计引物(上海生工合成)，在上游引物的5′端加上40bp的[GC]夹。对84名单纯性马蹄内翻足患者DNA目的片段进行PCR扩增，并用1.5％的琼脂糖凝胶电泳检测。
(2) DGGE检测以变性剂浓度范围为20％—80％的聚丙烯酰胺凝胶做水平DGGE，并根据带形及其位置进一步调节变性剂浓度范围及电泳时间；电泳后，下胶，溴化乙锭染色，在紫外灯下观察结果。
(3)确定突变位点对电泳带形异常的PCR产物进行DNA测序以确定序列改变的位置与性质，并对正常人DNA的相同位点进行筛查，以判断该碱基置换是突变还是多态。
实验结果
一、模型胎鼠RT-PCR结果
RT-PCR结果显示在模型胎鼠后肢发育的各个时期均存在Collal基因表达的上调。
二、人COLlAl基因RT-PCR结果
ICTEV患儿肌肉及肌腱组织中COLlAl基因表达水平高于正常组织。
三、PCR-DGGE检测结果
经DGGE筛查并测序发现一名患者-161bp处存在C→T的杂合突变，另一名患者+274bp处存在C→G的纯合突变。分别经过对100名正常人的同一位点进行筛查，没有发现相同的改变，排除其为多态。经查找人类基因突变数据库(The Human Gene Mutation Database，HGMD)，证实是尚未见报道的新突变。
结论
1、应用半定量RT-PCR的方法发现在马蹄内翻足模型胎鼠后肢发育的不同时期均存在Collal基因表达的上调，同时发现单纯性马蹄内翻足患儿患侧肌肉及肌腱组织中COLlAl基因表达水平高于正常组织，证明了该基因与马蹄内翻足畸形的发生具有相关性。
2、在COLlAl基因-161bp处和+274bp处发现了新突变，提示该基因转录调控序列的突变可能是ICTEV的致病原因之一。
Objective
Idiopathic congenital talipes equinovarus (ICTEV) is a complex footdeformity presented at birth with 0.6‰～1‰birth rate in Chinese.The cause ofICTEV remains controversial. Many factors as skeleton development anomaly,neuromuscular disease,developmental arrest in uterus and so on seem to beresponsible. It is considered that the genetic factors play an important role in thepathogenesis of ICTEV, and the heritability of ICTEV is about 65%, it is yetunknown about the hereditary patterns and penetrance of ICTEV.Recently, it isbelieved that abnormal expression of some limb development-related genes leadsto ICTEV. At present,researches on human ICTEV mainly focus on manysyndromes with foot malformations,and little advances have been made in theresearches on the susceptibility genes of ICTEV. The researches provid somecandidate regions and genes for ICTEV such as 5q15-31.1,10p11.2-15 and soon,which provide an useful clue for us to look for the candidate genes of ICTEV.
Researches indicat that the content of typeⅠcollagen is remarkable increasedin ICTEV.TypeⅠcollagen is the most abundant and widly expressed collagen inhuman. It provides the structural support for the body in skeleton, skin, bloodvessele,nerves,intestines,and in the fibous capsules of organs. TypeⅠcollagen is aheterotrimer of two identicalαl(Ⅰ) chains and one chα2(Ⅰ) chain. Theαl(Ⅰ) andchα2(Ⅰ) chains of typeⅠcollagen are encoded by the unlinked loci COL1A1 andCOL1A2 respectively. COL1A1 and COL1A2 locate in 17q21.3-q22 and7q21.3-q22 respectively.Now, it has discovered hundred of mutations in COL1A1gene.Mutations at these loci result primarily in the connective tissue disorders: osteogenesis imperfecta,Ehler-Danlos syndrome typesⅦA andⅦB,Osteoporosis.But there is no report about association between COL1A1 andICTEV.In our study, we will probe into the association between COL1A1 andICTEV furtherly on molecular level.
In our studies,we constructed animal model of talipes equinovarus withWistar rats, and discovered that there was up-regulation of Collal gene expressionin different stage of limb development in the animal model by RT-PCR. Then,wealso discovered that there was up-regulation of COL1A1 gene expression in themusclar and tenden tissues of ICTEV patients by RT-PCR. At the sametime,mutation sites in transcription regular sequences(-1031bp～+30bp) and intron1 of COL1A1 gene were detected in 84 patients with ICTEV by denaturinggradient gel electrophoresis technique.The result was that we found a -161C→Theterozygous mutation and a +274C→G homozygous mutation in COL1A1gene.So,we thought COL1A1 gene was confirmed to be associated with ICTEV.
Material and Methods
1. Samples
86 Wistar rats were bought from the animal department of China MedicalUniversity.
Musclar and tenden tissues of 20 patients with ICTEV and correspondingnormal tissues came from the Second Affiliated Hospital, China MedicalUniversity.
84 patients with ICTEV came from the Second Affiliated Hospital, ChinaMedical University. All patients had typical manifestation and were confirmed byX-rays and surgical operation. 100 normal DNA come from normal crowd ofnortheastern china.
2.Construction of rat model and Study Collal gene in thehindlimbs of rat models with RT-PCR
135mg/kg body weight of ATRA was used to construct rat model on day 10 ofgestation, which has shown a good consistency with talipes equinovarusmalformation as that in humans. On day 15、17、19 and 21 of gestation,thehindlimbs were cut from model fetus and normal controls,and total RNA was extracted,then reverse transcribed to cDNA. RT-PCR was used to detecte theexpression of COL1A1.
3.Study COL1A1 gene in musclar and tenden tissues of ICTEVwith RT-PCR
The total RNA was extracted from musclar and tenden tissues of patients withICTEV and normal controls,then reverse transcribed to cDNA. RT-PCR was usedto detecte the expression of COL1A1.
4.PCR-DGGE
Mutation sites in transcription regular sequences(-1031bp～+30bp) andintron 1 of COL1A1 gene were detected in 84 patients with ICTEV by denaturinggradient gel electrophoresis technique.
Results
1.The expression of Collal gene in rat models
RT-PCR results found the expression of Collal gene up-regulated in differentstage of limb development in rat models with the clubfoot like deformity.
2. The expression of COL1A1 gene in muscles and tenden ofpatients with ICTEV
RT-PCR results found the expression of COL1A1 gene in musclar and tendentissues of ICTEV is higher than normal tissues.
3. Result of PCR-DGGE
The result was that we found a-161C→T heterozygous mutation and a+274C→G homozygous mutation in COL1A1 gene.
Conclusions
1.RT-PCR results found the expression of Collal gene up-regulated indifferent stage of limb development, and the expression of COL1A1 geneup-regulated in musclar and tenden tissues of patients with ICTEV,whichconfirmed the association between COL1A1 gene and talipes equinovarusdeformation.
2. We discovered a-161T→C heterozygous mutation and a +274C→Ghomozygous mutation in COL1A1 gene of patients with ICTEV. It illustrated that the mutation in transcription regular sequences could caused ICTEV.
引文
1 梁娟，王艳萍，吴艳乔等．中国730例特发性马蹄内翻足发生率的流行病学调查．职业卫生与病伤．2000年，(第15卷)第2期：125-126．
2 Miedzybrodzka Z. Congenital talipes equinovarus(clubfoot): a disorder of the foot but not the hand. J. Anat, (2003)202 : 37-42.
3 Chapman C, Stott NS, Port RV, et al. Genetics of clubfoot in Maori and Pacific people. J Med Genet. 2000, Sep; 37(9) : 680-683.
4 王莉莉，金春莲，刘丽英等．5’HOXD基因与单纯性马蹄内翻足的相关性分析．中华医学遗传学杂志．2005，22(6)：653-656．
5 张炫，金春莲，刘丽英等．Gli3基因与单纯性马蹄内翻足的关联分析及其突变筛查．中华医学遗传学杂志．2006，23 (5)，551-554．
6 刘丽英，金春莲等．COL9A1基因与先天性马蹄内翻足相关性的研究．遗传．2007，29 (4)：427-432
7 Ippolito E. Congenital clubfoot in the human fetus. J Bone Joint Surg Am. 1980, Jan; 62 (1) : 8-22.
8 Dalgleish R, et al, The Human Collagen Mutation Database 1998. Nucleic Acid Res. 1998, 26(1) : 253-255.
9 Prockop DJ, Kivirikko KI. Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem. 1995, 64: 403-434.
10 Vuorio E, de Crombrugghe B. The family of collagen genes. Annu Rev Biochem. 1990, 59: 837-872.
11 Pepe G, Bue C, Orlandi P, et al, Are the SSTR alleles stable enough to be considered monop-hyletic and hence reliable anthropogenetic markers? Linkage disequilibrium study on the (ACT)n COL1A2 SSTR. Hum Biol. 1995, 67: 703-715.
12 Forlino A, Marini JC. Osteogenesis imperfecta: prospects for molecular therapeutics. Molecular Genetics and Metabolism. 2000, 71 (1-2) : 225-232.
13 Zimny ML, et al. An electon microscopic study of the fascia from the medial and lateral sides of clubfoot. J Pediatr Orthop. 1985, 5: 577-581.
14 Sano H, et al. Pathogenesis of soft-tissue contracture in club foot. J Bone Joint Surg Br. 1998, 80(4) : 641-644.
15 赵东风，岳勇，赵黎等．先天性马蹄内翻足患者深筋膜超微结构观察．中国临床康 复．2004，8(8)：1504-1505．
16 赵东风，岳勇，黄耀添等．先天性马蹄内翻足深筋膜胶原的免疫组化研究．中华小儿外科杂志．2004，25 (2)：182-184．
17 Sunder Raj CV, Church RL, et al. Genetics of the connective tissue proteins: assignment of the gene for human type I procollagen to chromosome 17 by analysis of cell hybrids and microcell hybrids. Proc Nat Acad Sci. 1977, 74: 4444-4448.
18 Church RL, SundarRaj N, Rohrbach DH. Gene mapping of human ocular connective tissue proteins. Assignment of the structural gene for corneal type I procollagen to human chromosome 7 in human corneal stroma-mouse fibroblast somatic cell hybrids. Invest Ophthalmol Vis Sci. 1981, 21: 73-79.
19 Huerre C, Junien C, et al. Human type I procollagen genes are located on different chromosomes. Proc Natl Acad Sci U S A. 1982, 79: 6627-6630.
20 Junien C, Huerre C, Rethore MO. Direct gene dosage determination in patients with unbalanced chromosomal aberrations using cloned DNA sequences. Application to the regional assignment of the gene for alpha 2(Ⅰ) procollagen (COLIA2). Am J Hum Genet. 1983, 35 (4) : 584-591.
21 Retief E, Parker MI, RetiefAE. Regional chromosome mapping of human collagen genes alpha 2(Ⅰ) and alpha 1(Ⅰ) (COLIA2 and COLIA1). Hum Genet.1985, 69(4) : 304-308.
22 Jimenez SA, Varga J, Olsen A, et al. Functional analysis of human α1 (Ⅰ) procollagen gene promoter. J Biol Chem. 1994, 269(17) : 12684-91.
23 Higashik K, Inagaki Y, et al. Y-box-binding protein YB-1 mediates transcriptional repression of human alpha 2(Ⅰ) collagen gene expression by interferon-gamma. J Biol Chem. 2003, 278: 5156-5162.
24 Wang L, Tankersley LR, et al. Regulation of the murine alpha(2)(Ⅰ) collagen promoter by retinoic acid and retinoid X receptors. Arch Biochem Biophy. 2002, 401: 262-270.
25 Falanga V, Zhou L, Yufit T. Low oxygen tension stimulates collagen synthesis and COL1A1 transcription through the action of TGF-betal. J Cell Physiol. 2002, Apr; 191(1) : 42-50.
26 Lindahl GE, Chambers RC, Papakrivopoulou J, et al. Activation of fibroblast procollagen alpha 1(Ⅰ) transcription by mechanical strain is transforming growth factor-beta-dependent and involves increased binding of CCAAT-binding factor (CBF/NF-Y) at the proximal promoter. J Biol Chem. 2002, 277(8) : 6153-6161.
27 Terraz C, Toman D, Delauche M, et al. delta Efl binds to a far upstream sequence of the mouse pro-alpha 1 (Ⅰ) collagen gene and represses its expression in osteoblasts. J Biol Chem. 2001, Oct 5; 276(40) : 37011-37019.
28 Miyazaki Y, et al. Dexamethasone inhibition of TGF beta-induced cell growth and type Ⅱ collagen mRNA expression through ERK-integrated AP-1 activity in cultured rat articular chondrocytes. Osteoarthritis Cartilage. 2000, Sep; 8(5) : 378-385.
29 Hernandez I, et al. Collagen alphal(Ⅰ) gene contains an element responsive to tumor necrosis factor-alpha located in the 5' untranslated region of its first exon. DNA Cell Biol. 2000, Jun; 19(6) : 341-352.
30 王皓，高春芳等．人α1(Ⅰ)胶原基因启动子活性研究．第二军医大学学报．2000，8：711-714．
31 高春芳等．人α2(Ⅰ)型胶原基因启动子活性研究．中华微生物与免疫学杂志．2002，1：55-61．
32 伍严安，高春芳等．胰岛素样生长因子1和胰岛素对人α1(Ⅰ)前胶原启动子活性的影响．中国免疫学杂志．2001，11：601-603．
33 高春芳，王皓等．小鼠α2(Ⅰ)胶原基因DNA结合蛋白研究．第二军医大学学报．2000，8：704-707．
34 伍严安，高春芳等．己酮可可碱对人α1(Ⅰ)前胶原基因启动子活性的影响．中华肝脏病杂志．2001，2：70-72．
35 高春芳，印彤等．细胞因子对小鼠α2(Ⅰ)型前胶原基因启动子活性影响的研究．中国免疫学杂志．1999，7：296-298．
36 高春芳，王皓等．干扰素对小鼠α2(Ⅰ)型胶原基因启动子活性的影响．世界华人消化杂志．1998，3：201-203．
37 Bornstein P, Mckay J. The first intron of the alpha 1(Ⅰ) collagen gene contains several transcriptional regulatory elements. J Biol Chem. 1988, 263 (4) : 1603-1606.
38 Bornstein P, Mckay J, et al. Regulatory elements in the first intron contribute to transcriptional control of the human alpha 1(Ⅰ) collagen gene. Proc Natl Acad Sci USA. 1987, 84 (24) : 8869-8873.
39 Rossouw CMS, et al. DNA sequences in the first intron of the human pro-alpha 1(Ⅰ) collagen gene enhance transcription. J Biol Chem. 1987, 262: 15151-15157.
40 Kakihara T, Fukuda T, Kamishima T, et al. Resistance to apoptosis induced by serum depletion and all-trans retinoic acid in drug-resistant leukemic cell lines. Leuk Lymphoma. 1997, 26(3-4) : 369-376.
41 Dhalla AK, Kandala JC, Weber KT, et al. Identification of negative and positive regulatory elements in the rat α1(Ⅰ) collagen gene promoter. Int J Biochem Cell Biol. 1997, 29(1):143-151.
42 Gao CF, Wang H, Huang C, et al.Study of activity of promoter from mouse α2(I) procollagen gene.Chinese Med J. 1999, 112(4):316-320.
43 Slachk JL, Liska D, Bornstein P.Regulation of expression of the type I collagen genes.Am J Med Genet. 1993, 45(2):140-151.
44 LapingNJ, Olson BA, Ho T, etal.Hepatocyte growth factor:a regulator of extracellular matrix genes in mouse mesangial cells.Biochem Pharmacol. 2000, 59(7):847-853.
45 Inagaki Y, Truter S, Tanaka S, et al .Overlapping pathways mediate the opposing actions of tumor necrosis factor-alpha and transforming growth factor-beta on alpha2(I) collagen transcription.J Biol Chem. 1995, 270(7):3353-3358.
46 Rippe RA, AlmounajedG, Brenner DA.SPl binding activity increases in activated I to cells.Hepatology. 1995, 22( 1 ):241 -251.
1 Dalgleish R. The Human Collagen Mutation Database 1998. Nucleic Acid Res. 1998, 26(1):253-255.
2 ProckopDJ, Kivirikko KI. Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem.1995, 64:403-434.
3 Vuorio E, de Crombrugghe B. The family of collagen genes .Annu Rev Biochem. 1990, 59:837 -872.
4 Pepe G, Bue C, Orlandi P, et al.Are the SSTR alleles stable enough to be considered monophyletic and hence reliable anthropogenetic markers? Linkage disequilibrium study on the (ACT)n COL1A2 SSTR.Hum Biol.1995, 67:703-715.
5 Forlino A, Marini JC. Osteogenesis imperfecta: prospects for molecular therapeutics. Mol Genet Metab. 2000, 71(1-2):225-232.
6 Sunder Raj CV , Church RL, et al.Genetics of the connective tissue proteins: assignment of the gene for human type I procollagen to chromosome 17 by analysis of cell hybrids and microcell hybrids.Proc Nat Acad Sci.1977, 74:4444-4448.
7 Church RL, SundarRaj N, Rohrbach DH. Gene mapping of human ocular connective tissue proteins. Assignment of the structural gene for corneal type I procollagen to human chromosome 7 in human corneal stroma-mouse fibroblast somatic cell hybrids. Invest Ophthalmol Vis Sci. 1981, 21:73-79.
8 Huerre C, Junien C, et al. Human type I procollagen genes are located on different chromosomes. Proc Natl Acad Sci U S A. 1982, 79:6627-6630.
9 Junien C, Huerre C, Rethore MO.Direct gene dosage determination in patients with unbalanced chromosomal aberrations using cloned DNA sequences. Application to the regional assignment of the gene for alpha 2(1) procollagen (COLIA2).Am J Hum Genet.1983, 35 (4):584-591.
10 Retief E, Parker MI, Retief AE. Regional chromosome mapping of human collagen genes alpha 2(I) and alpha 1(I) (COLIA2 and COLIA1).Hum Genet. 1985 , 69(4)::304-308.
11 Higashik K, Inagaki Y, et al. Y-box-binding protein YB-1 mediates transcriptional repression of human alpha 2(I) collagen gene expression by interferon-gamma.J Biol Chem.2003, 278:5156-5162.
12 Wang L, Tankersley LR, et al.Regulation of the murine alpha(2)(I) collagen promoterby retinoic acid and retinoid X receptors.Arch Biochem Biophy.2002, 401:262-270.
13 Falanga V, Zhou L, Yufit T. Low oxygen tension stimulates collagen synthesis and COL1A1 transcription through the action of TGF-betal. J Cell Physiol. 2002, Apr; 191(1) : 42-50.
14 Lindahl GE, Chambers RC, Papakrivopoulou J, et al. Activation of fibroblast procollagen alpha 1(Ⅰ) transcription by mechanical strain is transforming growth factor-beta-dependent and involves increased binding of CCAAT-binding factor (CBF/NF-Y) at the proximal promoter. J Biol Chem. 2002, 277(8) : 6153-6161.
15 Terraz C, Toman D, Delauche M, et al. delta Efl binds to a far upstream sequence of the mouse pro-alpha 1(Ⅰ) collagen gene and represses its expression in osteoblasts. J Biol Chem. 2001, Oct 5; 276(40) : 37011-37019.
16 Miyazaki Y, et al. Dexamethasone inhibition of TGF beta-induced cell growth and type Ⅱ collagen mRNA expression through ERK-integrated AP-1 activity in cultured rat articular chondrocytes. Osteoarthritis Cartilage. 2000, Sep; 8(5) : 378-385.
17 Hernandez I, et al. Collagen alphal(Ⅰ) gene contains an element responsive to tumor necrosis factor-alpha located in the 5'untranslated region of its first exon. DNA Cell Biol. 2000, Jun; 19(6) : 341-352.
18 王皓，高春芳等．人α1(Ⅰ)胶原基因启动子活性研究．第二军医大学学报．2000，8：711-714．
19 高春芳等．人α2(Ⅰ)型胶原基因启动子活性研究．中华微生物与免疫学杂志．2002，1：55-61．
20 伍严安，高春芳等．胰岛素样生长因子1和胰岛素对人α1(Ⅰ)前胶原启动子活性的影响．中国免疫学杂志．2001，11：601-603．
21 高春芳，王皓等．小鼠α2(Ⅰ)胶原基因DNA结合蛋白研究．第二军医大学学报．2000，8：704-707．
22 伍严安，高春芳等．己酮可可碱对人α1(Ⅰ)前胶原基因启动子活性的影响．中华肝脏病杂志．2001，2：70-72．
23 高春芳，印彤等．细胞因子对小鼠α2(Ⅰ)型前胶原基因启动子活性影响的研究．中国免疫学杂志．1999，7：296-298．
24 高春芳，王皓等．干扰素对小鼠α2(Ⅰ)型胶原基因启动子活性的影响．世界华人消化杂志．1998，3：201-203．
25 Bornstein P, Mckay J. The first intron of the alpha 1(Ⅰ) collagen gene contains several transcriptional regulatory elements. J Biol Chem. 1988, 263 (4) : 1603-1606.
26 Bornstein P, Mckay J, et al. Regulatory elements in the first intron contribute to transcriptional control of the human alpha 1(I) collagen gene. Proc Natl Acad Sci USA.1987, 84 (24):8869- 8873.
27 Rossouw CMS, et al.DNA sequences in the first intron of the human pro-alpha 1(1) collagen gene enhance transcription.J Biol Chem.1987, 262:15151-15157.
28 Chu M L, et al. Internal deletion in a collagen gene in a perinatal lethal form of osteogenesis imperfecta.Nature.1983, 304(5921):78-80.
29 Dalgleish R. The human type I collagen mutation database.Nucleic Acid Res. 1997, 25(1):181- 187.
30 RauchF, Glorieux FH. Osteogenesis imperfecta.The LANCET.2004, 363:1377-1385.
31 Nuylinck L, et al. Prenatal diagnosis of osteogenesis imperfecta type I by COLI A1 null-allele testing.Prenat Diagn.1999, 19(9):873-875.
32 Willing MC, Deschenes SP , et al. Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen. Am J Hum Genet. 1994, 55:638-647.
33 Willing MC, Deschenes SP, SlaytonRL, Robeerts EJ. Premature chain termination is a unifying mechanism for COL1A1 null alleles in osteogenesis imperfecta type I cell strains. Am J Hum Genet.1996, 59:799-809.
34 Willing MC, Pruchno CJ,Atkinson M, et al.Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele of type I collagen.Am J Hum Genet. 1992, 51:508- 515.
35 Redford-Badwal DA, Stover ML, et al. Nuclear retention of COL1A1 messenger RNA identifies null alleles causing mild osteogenesis imperfecta.DWJ Clin Invest. 1996, 97: 1035-1040.
36 Kuznetsova NV, Forlino A, et al. Structure, stability and interactions of type I collagen with GLY349-CYS substitution in alpha 1(I) chain in a murine Osteogenesis Imperfecta model.Matrix Biology.2004, 23:101-112.
37 Lichtenstein JR, Martin GR , et al. Defect in conversion of procollagen to collagen in a form of Ehlers-Danlos syndrome. Science.1973, 182(109):298-300.
38 Steinmann B, Tuderman L, et al. Evidence for a structural mutation of procollagen type I in a patient with the Ehlers-Danlos syndrome type VII. J Biol Chem.1980, 255(18): 8887-8893.
39 Eyre DR, Shapiro FD, Aldridge JF. A heterozygous collagen defect in a variant of the Ehlers-Danlos syndrome type VII. Evidence for a deleted amino-telopeptide domain in the pro-alpha 2(I) chain.J Biol Chem.1985, 260(20):11322 -11329.
40 Cole WG, Chan D, Chambers GW, et al. Deletion of 24 amino acids from the pro-alpha 1 (Ⅰ) chain of type Ⅰ procollagen in a patient with the Ehlers-Danlos syndrome type Ⅶ. J Biol Chem. 1986, 261: 5496-5503.
41 Wirtz MK, et al. Ehlers-Danlos syndrome type ⅦB. Deletion of 18 amino acids comprising the N-telopeptide region of a pro-alpha 2(Ⅰ) chain. J Biol Chem. 1987, 262: 16376-16385.
42 Phillips, et al. A substitution at a non-glycine position in the triple-helical domain of pro alpha 2(Ⅰ) collagen chains present in an individual with a variant of the Marfan syndrome. J Clin Inverst. 1990, 86: 1723-1728.
43 Spotila LD, et al. Mutation in a gene for type I procollagen (COL1A2) in a woman with postmenopausal osteoporosis: evidence for phenotypic and genotypic overlap with mild osteogenesis imperfecta. Proc Natl Acad Sci USA. 1991, 88: 5423-5427.
44 Zimny ML, et al. An electon microscopic study of the fascia from the medial and lateral sides of clubfoot. J Pediatr Orthop. 1985, 5: 577-581.
45 Sano H, et al. Pathogenesis of soft-tissue contracture in club foot. J Bone Joint Surg Br. 1998, 80(4) : 641-644.
46 赵东风，岳勇，赵黎等．先天性马蹄内翻足患者深筋膜超微结构观察．中国临床康复．2004，8(8)：1504-1505．
47 赵东风，岳勇，黄耀添等．先天性马蹄内翻足深筋膜胶原的免疫组化研究．中华小儿外科杂志．2004，25(2)：182-184．
48 Khan AM, et al. Connective tissue structures in clubfoot: a morphologic study. J Pediat Orthop. 2001, 21(6) : 708-712.
2 Miedzybrodzka Z. Congenital talipes equinovarus(clubfoot): a disorder of the foot but not the hand. J. Anat, (2003)202 : 37-42.
3 Chapman C, Stott NS, Port RV, et al. Genetics of clubfoot in Maori and Pacific people. J Med Genet. 2000, Sep; 37(9) : 680-683.
4 王莉莉，金春莲，刘丽英等．5’HOXD基因与单纯性马蹄内翻足的相关性分析．中华医学遗传学杂志．2005，22(6)：653-656．
5 张炫，金春莲，刘丽英等．Gli3基因与单纯性马蹄内翻足的关联分析及其突变筛查．中华医学遗传学杂志．2006，23 (5)，551-554．
6 刘丽英，金春莲等．COL9A1基因与先天性马蹄内翻足相关性的研究．遗传．2007，29 (4)：427-432
7 Ippolito E. Congenital clubfoot in the human fetus. J Bone Joint Surg Am. 1980, Jan; 62 (1) : 8-22.
8 Dalgleish R, et al, The Human Collagen Mutation Database 1998. Nucleic Acid Res. 1998, 26(1) : 253-255.
9 Prockop DJ, Kivirikko KI. Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem. 1995, 64: 403-434.
10 Vuorio E, de Crombrugghe B. The family of collagen genes. Annu Rev Biochem. 1990, 59: 837-872.
11 Pepe G, Bue C, Orlandi P, et al, Are the SSTR alleles stable enough to be considered monop-hyletic and hence reliable anthropogenetic markers? Linkage disequilibrium study on the (ACT)n COL1A2 SSTR. Hum Biol. 1995, 67: 703-715.
12 Forlino A, Marini JC. Osteogenesis imperfecta: prospects for molecular therapeutics. Molecular Genetics and Metabolism. 2000, 71 (1-2) : 225-232.
13 Zimny ML, et al. An electon microscopic study of the fascia from the medial and lateral sides of clubfoot. J Pediatr Orthop. 1985, 5: 577-581.
14 Sano H, et al. Pathogenesis of soft-tissue contracture in club foot. J Bone Joint Surg Br. 1998, 80(4) : 641-644.
15 赵东风，岳勇，赵黎等．先天性马蹄内翻足患者深筋膜超微结构观察．中国临床康 复．2004，8(8)：1504-1505．
16 赵东风，岳勇，黄耀添等．先天性马蹄内翻足深筋膜胶原的免疫组化研究．中华小儿外科杂志．2004，25 (2)：182-184．
17 Sunder Raj CV, Church RL, et al. Genetics of the connective tissue proteins: assignment of the gene for human type I procollagen to chromosome 17 by analysis of cell hybrids and microcell hybrids. Proc Nat Acad Sci. 1977, 74: 4444-4448.
18 Church RL, SundarRaj N, Rohrbach DH. Gene mapping of human ocular connective tissue proteins. Assignment of the structural gene for corneal type I procollagen to human chromosome 7 in human corneal stroma-mouse fibroblast somatic cell hybrids. Invest Ophthalmol Vis Sci. 1981, 21: 73-79.
19 Huerre C, Junien C, et al. Human type I procollagen genes are located on different chromosomes. Proc Natl Acad Sci U S A. 1982, 79: 6627-6630.
20 Junien C, Huerre C, Rethore MO. Direct gene dosage determination in patients with unbalanced chromosomal aberrations using cloned DNA sequences. Application to the regional assignment of the gene for alpha 2(Ⅰ) procollagen (COLIA2). Am J Hum Genet. 1983, 35 (4) : 584-591.
21 Retief E, Parker MI, RetiefAE. Regional chromosome mapping of human collagen genes alpha 2(Ⅰ) and alpha 1(Ⅰ) (COLIA2 and COLIA1). Hum Genet.1985, 69(4) : 304-308.
22 Jimenez SA, Varga J, Olsen A, et al. Functional analysis of human α1 (Ⅰ) procollagen gene promoter. J Biol Chem. 1994, 269(17) : 12684-91.
23 Higashik K, Inagaki Y, et al. Y-box-binding protein YB-1 mediates transcriptional repression of human alpha 2(Ⅰ) collagen gene expression by interferon-gamma. J Biol Chem. 2003, 278: 5156-5162.
24 Wang L, Tankersley LR, et al. Regulation of the murine alpha(2)(Ⅰ) collagen promoter by retinoic acid and retinoid X receptors. Arch Biochem Biophy. 2002, 401: 262-270.
25 Falanga V, Zhou L, Yufit T. Low oxygen tension stimulates collagen synthesis and COL1A1 transcription through the action of TGF-betal. J Cell Physiol. 2002, Apr; 191(1) : 42-50.
26 Lindahl GE, Chambers RC, Papakrivopoulou J, et al. Activation of fibroblast procollagen alpha 1(Ⅰ) transcription by mechanical strain is transforming growth factor-beta-dependent and involves increased binding of CCAAT-binding factor (CBF/NF-Y) at the proximal promoter. J Biol Chem. 2002, 277(8) : 6153-6161.
27 Terraz C, Toman D, Delauche M, et al. delta Efl binds to a far upstream sequence of the mouse pro-alpha 1 (Ⅰ) collagen gene and represses its expression in osteoblasts. J Biol Chem. 2001, Oct 5; 276(40) : 37011-37019.
28 Miyazaki Y, et al. Dexamethasone inhibition of TGF beta-induced cell growth and type Ⅱ collagen mRNA expression through ERK-integrated AP-1 activity in cultured rat articular chondrocytes. Osteoarthritis Cartilage. 2000, Sep; 8(5) : 378-385.
29 Hernandez I, et al. Collagen alphal(Ⅰ) gene contains an element responsive to tumor necrosis factor-alpha located in the 5' untranslated region of its first exon. DNA Cell Biol. 2000, Jun; 19(6) : 341-352.
30 王皓，高春芳等．人α1(Ⅰ)胶原基因启动子活性研究．第二军医大学学报．2000，8：711-714．
31 高春芳等．人α2(Ⅰ)型胶原基因启动子活性研究．中华微生物与免疫学杂志．2002，1：55-61．
32 伍严安，高春芳等．胰岛素样生长因子1和胰岛素对人α1(Ⅰ)前胶原启动子活性的影响．中国免疫学杂志．2001，11：601-603．
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