JAG1基因在先天性心脏病中的突变及表达研究
摘要
目的
先天性心脏病(congenital heart disease,CHD)是胎儿期心脏及大血管发育异常而致的先天畸形,是一种最常见的出生缺陷,严重危害婴幼儿健康,发病率接近1%,在流产儿和死胎中则高达10%,在新生儿非感染性死亡疾病中占首位。80%的先天性心脏病表现为单纯性先天性心脏病(即不伴有其他系统的先天异常),其中圆锥动脉干畸形占1/4-1/3。多年来已经证实CHD是一种多基因遗传病,主要由于胚胎期遗传因素和环境因素共同作用导致心脏血管异常发育所引起的,遗传度为55%-65%。JAG1基因编码Notch家族受体配体蛋白jagged1蛋白,该基因在人类胚胎发育中起着重要作用,主要在心血管系统表达,突变率较高,目前已发现有200余种突变存在。国外研究认为JAG1基因是Alagille综合征(Alagillesyndrome,AGS,先天性肝胆管发育不良综合征,主要包括5个特征性表现:小叶间胆管缺乏、周围肺动脉狭窄、蝶样椎骨、角膜后胚胎环以及特殊面容)的致病基因,而在CHD中的研究尚局限于AGS中,有关JAG1基因与单纯性CHD的相关性尚未见明确报道。因此,本研究通过筛查该基因在单纯性CHD心肌组织中的突变及表达情况,探讨JAG1基因与单纯性CHD发病机制的关系。
方法
采用PCR-SSCP(polymerase chain reaction and single strand conformationpolymorphism,PCR-SSCP,聚合酶链反应-单链构象多态性)方法对30例单纯性CHD引产胎儿心肌组织进行JAG1基因外显子2、4、5、6的突变筛查;以β-actin为内对照,采用RT-PCR方法检测JAG1基因在单纯性CHD心肌组织中的表达情况。
结果
所有单纯性CHD引产胎儿心肌组织标本中所选的4个外显子PCR扩增产物经SSCP检测后,未发现体细胞突变;与正常心肌组织相比,单纯性CHD引产胎儿心肌组织中JAG1基因mRNA表达呈下降趋势(P<0.05)。
结论
1、JAG1基因外显子2、4、5、6编码区的突变可能不是单纯性CHD的致病原因。
2、JAG1基因转录水平的异常可能是其参与CHD发生的一种潜在机制。
Objective
Congenital heart disease(CHD) is a kind of congenital malformation caused by heart and major vessels ' abnormal development in fetal period.It is a kind of most common newborn defects,affects approximately 1%of infants,its incidence is estimated at close to ten times that level among abortus and stillbirths.CHD is the most common cause of noninfectious death in newborns.80%of CHD appears isolated CHD (other systems are normal).About 1/4-1/3 of CHD are conotruncal heart malformation. Studies have proved that CHD is a cardiac and vascular malfomation of multifactorial inheritance,which caused by genetic factors in embryonic phase and environmental factors,and the heritability is from 55%to 65%.JAG1 gene encodes a ligand of Notch receptor in the evolutionarily conserved Notch signaling pathway.It is very important in the embryonic development of homo-spapiens,it expresses in cardiovascular system mainly,the mutation rate is higher than other genes,now,there are more than 200 kinds of mutations have been found.The rearches of aboard presume that JAG1 gene is the virulence gene of Alagille syndrome(AGS,the major symptoms are:cholestasis, vertebral deformity,heart malformations,ocular defects and peculiar facial appearance), and the researches about JAG1 gene on CHD are limited in AGS,there are little identified reports are seen about JAG1 gene in isolated CHD.Through screening the mutations of JAG1 gene in isolated CHD and analyzing the expression levels of JAG1 gene in the cardiac muscular tissues,we want to approach the relationships between JAG1 gene and the pathogenesies in isolated CHD.
Method
Screen the mutations of the coding sequences of JAG1 gene in 30 myocardium samples from the fetuses with isolated CHD by PCR-SSCP method;Using P-actin as internal control,we detected the differential expression between 30 myocardium samples from isolated CHD fetuses and 30 normal controls by reverse transcription polymerase chain reaction(RT-PCR).
Results
No mutations were detected in exon2,4,5,6 of JAG1 gene in all samples by PCR-SSCP;The mRNA expression levels of JAG1 gene show descendent tendency in the samples of isolated CHD compared with normal controls.
Conclusion
1.Mutations in coding regions of exon2,4,5,6 of JAG1 gene may not cause human isolated congenital heart disease.
2.The abnormality in transcription level of JAG1 gene may be a kind of mechanism causing human isolated congenital heart disease.
先天性心脏病(congenital heart disease,CHD)是胎儿期心脏及大血管发育异常而致的先天畸形,是一种最常见的出生缺陷,严重危害婴幼儿健康,发病率接近1%,在流产儿和死胎中则高达10%,在新生儿非感染性死亡疾病中占首位。80%的先天性心脏病表现为单纯性先天性心脏病(即不伴有其他系统的先天异常),其中圆锥动脉干畸形占1/4-1/3。多年来已经证实CHD是一种多基因遗传病,主要由于胚胎期遗传因素和环境因素共同作用导致心脏血管异常发育所引起的,遗传度为55%-65%。JAG1基因编码Notch家族受体配体蛋白jagged1蛋白,该基因在人类胚胎发育中起着重要作用,主要在心血管系统表达,突变率较高,目前已发现有200余种突变存在。国外研究认为JAG1基因是Alagille综合征(Alagillesyndrome,AGS,先天性肝胆管发育不良综合征,主要包括5个特征性表现:小叶间胆管缺乏、周围肺动脉狭窄、蝶样椎骨、角膜后胚胎环以及特殊面容)的致病基因,而在CHD中的研究尚局限于AGS中,有关JAG1基因与单纯性CHD的相关性尚未见明确报道。因此,本研究通过筛查该基因在单纯性CHD心肌组织中的突变及表达情况,探讨JAG1基因与单纯性CHD发病机制的关系。
方法
采用PCR-SSCP(polymerase chain reaction and single strand conformationpolymorphism,PCR-SSCP,聚合酶链反应-单链构象多态性)方法对30例单纯性CHD引产胎儿心肌组织进行JAG1基因外显子2、4、5、6的突变筛查;以β-actin为内对照,采用RT-PCR方法检测JAG1基因在单纯性CHD心肌组织中的表达情况。
结果
所有单纯性CHD引产胎儿心肌组织标本中所选的4个外显子PCR扩增产物经SSCP检测后,未发现体细胞突变;与正常心肌组织相比,单纯性CHD引产胎儿心肌组织中JAG1基因mRNA表达呈下降趋势(P<0.05)。
结论
1、JAG1基因外显子2、4、5、6编码区的突变可能不是单纯性CHD的致病原因。
2、JAG1基因转录水平的异常可能是其参与CHD发生的一种潜在机制。
Objective
Congenital heart disease(CHD) is a kind of congenital malformation caused by heart and major vessels ' abnormal development in fetal period.It is a kind of most common newborn defects,affects approximately 1%of infants,its incidence is estimated at close to ten times that level among abortus and stillbirths.CHD is the most common cause of noninfectious death in newborns.80%of CHD appears isolated CHD (other systems are normal).About 1/4-1/3 of CHD are conotruncal heart malformation. Studies have proved that CHD is a cardiac and vascular malfomation of multifactorial inheritance,which caused by genetic factors in embryonic phase and environmental factors,and the heritability is from 55%to 65%.JAG1 gene encodes a ligand of Notch receptor in the evolutionarily conserved Notch signaling pathway.It is very important in the embryonic development of homo-spapiens,it expresses in cardiovascular system mainly,the mutation rate is higher than other genes,now,there are more than 200 kinds of mutations have been found.The rearches of aboard presume that JAG1 gene is the virulence gene of Alagille syndrome(AGS,the major symptoms are:cholestasis, vertebral deformity,heart malformations,ocular defects and peculiar facial appearance), and the researches about JAG1 gene on CHD are limited in AGS,there are little identified reports are seen about JAG1 gene in isolated CHD.Through screening the mutations of JAG1 gene in isolated CHD and analyzing the expression levels of JAG1 gene in the cardiac muscular tissues,we want to approach the relationships between JAG1 gene and the pathogenesies in isolated CHD.
Method
Screen the mutations of the coding sequences of JAG1 gene in 30 myocardium samples from the fetuses with isolated CHD by PCR-SSCP method;Using P-actin as internal control,we detected the differential expression between 30 myocardium samples from isolated CHD fetuses and 30 normal controls by reverse transcription polymerase chain reaction(RT-PCR).
Results
No mutations were detected in exon2,4,5,6 of JAG1 gene in all samples by PCR-SSCP;The mRNA expression levels of JAG1 gene show descendent tendency in the samples of isolated CHD compared with normal controls.
Conclusion
1.Mutations in coding regions of exon2,4,5,6 of JAG1 gene may not cause human isolated congenital heart disease.
2.The abnormality in transcription level of JAG1 gene may be a kind of mechanism causing human isolated congenital heart disease.
引文
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2 Debrus S, BergerG, deMeeusA, et al. Familial non-syndromic conotruncal defects are not associated with a 22qll microdeletion. Hum Genet.1996, 97: 138-144.
3 Gong LG, Qiu GR, Jiang H, et al. Analysis of single nucleotide polymorphisms and haplotypes in HOXC gene cluster within susceptible region 12ql3 of isolated congenital heart disease [J]. Chin J M ed Genet, 2005, 22 (50): 2972501.
4 Piccoli DA, Spinner NB. Alagille syndrome and the Jaggedl gene. Semin Liver Dis. 2001 Nov, 21(4): 525-34.
5 Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jaggedl, which encodes a ligand for Notchl. Nature Genet .1997, 16:243-251.
6 Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jaggedl gene are responsible for Alagille syndrome. Nature Genet. 1997, 16:235-242.
7 Krantz ID, CollitonRP, Genin A, et al. Spectrum and frequency of Jaggedl (JAG1) mutations in Alagille syndrome patients and their families. Aid J Hum Genet. 1998,62:1361-1369.
8 Giannakudis J, Ropke A, Kujat A, et al. Parental mosaicism of JAG1 mutations in families with Alagille syndrome. Eur J Hum Genet.2001, 9:209-216.
9 Yuan ZR, Okaniwa M, Nagata I, et al. The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome. Clin Genet.2001, 59:330-337.
10 Crosnier C, Driancourt C, Raynaud N, et al. Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome. Hum Mutat. 2000, 17:72-73.
11 Colliton RP, Bason L, Lu FM, et al. Mutation analysis of Jaggedl (JAG1) in Alagille syndrome patients. Hum Mutat. 2001, 17(2):151-2.
12 Yuan ZR, Kohsaka T, Ikegaya T, et al. Mutational analysis of the Jaggedl gene in Alagille syndrome families. Hum Mol Genet. 1998,7:1363-1369.
13 Crosnier C, Driancourt C, Raynoud N, et al. Mutations in Jaggedl gene are predominantly sporadic in Alagille syndrome. Gastroenterology. 1999, 116:1141-1148.
14 Onouchi Y, Kurahashi H, Tajiri H, et al. Genetic alterations in the JAG1 gene in Japanese patients with Alagille syndrome.J Hum Genet.1999,44:235-239.
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2 Debrus S,Berger G,de Meeus A,Sauer U,et al.Familial non-syndromic conotruncal defects are not associated with a 22q11 microdeletion.Hum Genet.1996,97:138-144.
3 Gong LG,Qiu GR,Jiang H,et al.Analysis of single nucleotide polymorphisms and haplotypes in HOXC gene cluster within susceptible region 12q13 of isolated congenital heart disease[J].Chin J Med Genet,2005,22(50):2972501.
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5 徐竹蔚,金伯泉。新的人类白细胞分化抗原(CD)的命名及其功能[J]。细胞与分子免疫学杂志。2005,21(3):395-397。
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13 Kamath BM, Spinner NB, Emerick KM, Chudley AE, et al. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation.2004, 23,109(11): 1354-8.
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15 Boyer J, Crosnier C, Driancourt C, Raynaud N et al. Expression of mutant JAGGED1 alleles in patients with Alagille syndrome. Hum Genet. 2005 May, 116(6):445-53.
16 Xue Y, Gao X, Lindsell CE, et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jaggedl [J]. Hum Mol Genet. 1999, 8(5):723-730.
17 Li H, Yu B, Zhang Y, et al. Jaggedl protein enhances the differentiation of mesenchymal stem cells into cardiomyocytes. Biochem Biophys Res Commun. 2006,10, 341(2):320-5.
18 McElhinney DB, Krantz ID, Bason L, Piccoli DA et al. Analysis of cardiovascular phenotype and genotype-phynotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome [J]. Circulation, 2002, 106(20):2567-2574.
19 Krantz ID, Smith R, Colliton RP, et al. Jaggedl mutations in patients ascertained with isolated congenital heart defects. Am J Med Genet. 1999, 7, 84(1):56-60.
20 Eldadah ZA, Hamosh A, Biery NJ, et al. Familial Tetralogy of Fallot caused by mutation in the jaggedl gene. Hum Mol Genet. 2001 Jan 15, 10(2):163-9.
21 Varnum-Finney B, Purton LE, Yu M, et al. The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells [J].Blood, 1998,91(11): 4084-4091.
22 Jones P, May G, Healy L, et al. Stromal expression of Jaggedl promotes colony formation by fetal hematopoietic progenitor cells [J]. Blood, 1998,92(5): 1505-1511.
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43 Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jaggedl, which encodes a ligand for Notchl. Nature Genet . 1997, 16:243-251.
44 Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jaggedl gene are responsible for Alagille syndrome. Nature Genet. 1997,16:235-242
45 Krantz ID, Colliton RP, Genin A, et al. Spectrum and frequency of Jaggedl (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet. 1998,62:1361-1369.
46 Giannakudis J, R(?)pke A, Kujat A, et al. Parental mosaicism of JAG1 mutations in families with Alagille syndrome. Eur J Hum Genet. 2001, 9:209-216.
47 Yuan ZR, Okaniwa M, Nagata I, et al. The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome. Clin Genet.2001,59:330-337.
48 Crosnier C, Driancourt C, Raynaud N, et al. Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome. Mutation in Brief # 385. Hum Mutat. 2000, 17:72-73.
49 CollitonRP, Bason L, Lu FM, et al. Mutation analysis of Jaggedl (JAGl) in Alagille syndrome patients. Hum Mutat. 2001, 17(2):151-2.
50 Yuan ZR, Kohsaka T, Ikegaya T, et al. Mutational analysis of the Jaggedl gene in Alagille syndrome families. Hum Mol Genet. 1998,7:1363-1369.
51 Crosnier C, Driancourt C, Raynoud N, et al. Mutations in Jaggedl gene are predominantly sporadic in Alagille syndrome. Gastroenterology. 1999, 116:1141-1148.
52 Onouchi Y, Kurahashi H, Tajiri H, et al. Genetic alterations in the JAGl gene in Japanese patients with Alagille syndrome. J Hum Genet. 1999, 44:235-239.
53 Pilia G, Uda M, Macis D, et al. Jagged-1 mutation analysis in Italian Alagille syndrome patients. Hum Mutat. 1999, 14(5):394-400.
54 Heritage ML, MacMillanJC, Anderson GJ. DHPLC mutation analysis of Jaggedl (JAGl) reveals six novel mutations in Australian Alagille syndrome patients. Hum Mutat.2002, 20(6): 481.
55 Ropke A, Kujat A, Graber M, et al. Identification of 36 novel Jaggedl (JAGl) mutations in patients with Alagille syndrome. Hum Mutat. 2003, 21(1):100.
56 Jurkiewicz D, Popowska E, Glaser C, Hansmann Ⅰ et al. Twelve novel JAGl gene mutations in Polish Alagille syndrome patients. 2005, 25(3):321.
2 Debrus S, BergerG, deMeeusA, et al. Familial non-syndromic conotruncal defects are not associated with a 22qll microdeletion. Hum Genet.1996, 97: 138-144.
3 Gong LG, Qiu GR, Jiang H, et al. Analysis of single nucleotide polymorphisms and haplotypes in HOXC gene cluster within susceptible region 12ql3 of isolated congenital heart disease [J]. Chin J M ed Genet, 2005, 22 (50): 2972501.
4 Piccoli DA, Spinner NB. Alagille syndrome and the Jaggedl gene. Semin Liver Dis. 2001 Nov, 21(4): 525-34.
5 Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jaggedl, which encodes a ligand for Notchl. Nature Genet .1997, 16:243-251.
6 Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jaggedl gene are responsible for Alagille syndrome. Nature Genet. 1997, 16:235-242.
7 Krantz ID, CollitonRP, Genin A, et al. Spectrum and frequency of Jaggedl (JAG1) mutations in Alagille syndrome patients and their families. Aid J Hum Genet. 1998,62:1361-1369.
8 Giannakudis J, Ropke A, Kujat A, et al. Parental mosaicism of JAG1 mutations in families with Alagille syndrome. Eur J Hum Genet.2001, 9:209-216.
9 Yuan ZR, Okaniwa M, Nagata I, et al. The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome. Clin Genet.2001, 59:330-337.
10 Crosnier C, Driancourt C, Raynaud N, et al. Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome. Hum Mutat. 2000, 17:72-73.
11 Colliton RP, Bason L, Lu FM, et al. Mutation analysis of Jaggedl (JAG1) in Alagille syndrome patients. Hum Mutat. 2001, 17(2):151-2.
12 Yuan ZR, Kohsaka T, Ikegaya T, et al. Mutational analysis of the Jaggedl gene in Alagille syndrome families. Hum Mol Genet. 1998,7:1363-1369.
13 Crosnier C, Driancourt C, Raynoud N, et al. Mutations in Jaggedl gene are predominantly sporadic in Alagille syndrome. Gastroenterology. 1999, 116:1141-1148.
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