成骨不全四家系基因突变检测及基因型表型关系分析
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摘要
成骨不全(Osteogenesis Imperfecta,OI)是一种全身性遗传性结缔组织疾病,根据其临床表现及体征的不同,目前分为7种类型,研究表明90%以上的OI患者具有工型胶原基因(COL1A1/COL1A2基因)的改变,其中尤以COL1A1基因的改变为主；OI的基因型表型关系目前还不十分明确,但分子遗传学研究表明,OI临床表现与突变基因具有一定的相关性,不同人种及家系的基因突变各有特点,并常常具有私有性突变。OI基因水平的研究目前已成为国内外研究的一个热点,迄今国外已报道了千余种导致OI表型的Ⅰ型胶原基因的突变,但在我国OI的研究仍主要停留在临床个案报道及影像学报告的阶段,基因突变水平的研究还比较少见。
目的
本研究选取国内4个OI先证者家系,通过临床查体、病史问询、家系调查及基因突变的检测,明确各家系中患病个体的临床诊断分型,寻找基因突变位点,明确遗传方式,并探讨中国人群OI基因型与表型的关系,以丰富中国人群在这方面的资料,为该病的诊断预防及遗传咨询工作奠定一定的基础,并为将来可能的基因治疗提供理论依据。
方法
本研究选取2008年6月至2009年6月就诊于郑州大学第三附属医院门诊的河南省内的四个OI先证者,分别对其家系患病成员及部分健康成员进行临床体格检查、病史及家系调查,以收集临床资料,绘制不同家系的遗传图谱,确定各家系的遗传方式,根据sillence提出的经典分型标准对各家系中患病个体进行临床诊断分型；然后经患者本人及家属知情同意,并经医院伦理委员会同意批准,抽取家系中患病成员及部分健康成员的外周血液标本,提取血液标本的白细胞基因组DNA,应用PCR扩增的方法对四个先证者的COL1A1/COL1A2上所有的启动子,外显子及外显子-内含子区域进行基因扩增及基因突变检测,应用DNA直接测序法对4例先证者的Ⅰ型胶原基因(COL1A1/COL1A2基因)片段进行测序,然后应用生物信息学软件对测序结果与Genbank标准序列进行对比分析,以寻找基因突变的位点及形式,最后根据四个先证者的基因检测结果,分别对各家系其他成员的血液标本进行COL1A1/COL1A2基因的突变检测及测序,并应用生物信息学软件加以分析。
结果
(1)临床诊断分型结果：先证者一诊断为Ⅳ型OI,先证者一母亲诊断为Ⅰ型OI；先证者二诊断为Ⅰ型OI；先证者三及其父亲,姑姑均诊断为Ⅰ型OI；先证者四及其母亲均为Ⅰ型OI。
(2)基因检测及测序结果：在先证者一及其家系患病个体中检测到COL1A1基因上第36外显子c.2473位点G>A的突变,先证者二在COL1A1基因上第26内含子剪切位点处检测到c.1821+1位点G>A的突变,先证者四及其家系患病个体中检测到COL1A1基因上第9个内含子剪切位点处c.697-2位点C>T的突变,先证者三及四个家系中所有非患病成员个体均未检测到COL1A1/COL1A2基因上的突变。
结论
(1)COL1A1基因的改变可以导致成骨不全,也是引起中国人群成骨不全的原因之一；
(2)对于中国人群,除COL1A1/COL1A2基因的改变外,还可能具有能够引起成骨不全临床表型的其他基因改变的存在；
(3)成骨不全的临床表型不仅与基因型有关,还受到遗传背景、个人体质,人种差异、外周环境及其他因素的影响。
Osteogenesis imperfecta (OI) is a systemic hereditary connective tissue disease, which is divided into 7 types according to clinical manifestations and signs. A research shows that over 90% of patients exhibit OI type.Ⅰcollagen gene (COL1A1 and COL1A2) change, especially in the COL1A1 gene. The relationship between its genotype and phenotype keep uncertain yet, but the molecular genetic studies show that OI clinical manifestations are relative to gene mutations certainly, and some differences exist between ethnics or families, owning its features with private mutations frequently; the research on OI gene levels has become a hot topic at home and abroad. So far in abroad, more than a thousand species of type I collagen gene mutations lead to OI have been reported, but our research still stay at a low level, such as clinical or imaging reports et al.There is lack of the research on gene mutation.
Objective
To find gene mutation sites, determine genetic pattern and diagnose indefinitely by clinical physical examination, family and genetic testing,4 OI proband families will be selected in this research. We will explore the relationship between OI genotype and phenotype, enrich Chinese population data in this regard, and provide a theoretical basis for its diagnosis, prevention, genetic counseling and futuristic gene therapy.
Methods
The four out-OI proband from Henan Province who were seen the Third Affiliated Hospital of Zhengzhou University from June 2008 to September 2009 were selected in this research. Their family members and some members were given some clinical health examination, some clinical data such as medical history and family surveys were collected, genetic maps of different pedigrees were drawn, genetic methods were determined, individual type and clinical diagnosis were established according to sillence classic classification proposed standards; Then by the patient and the family agreed, and approved by the hospital ethics committee, affected family members and some healthy members of the peripheral blood were taken, genomic DNA of white blood cells were extracted, PCR amplification method of application of the four proband all those who COLlA1/COL1A2 promoter, exon and exon-intron region gene amplification and gene mutation, and then the DNA sequencing were applied for four cases of proband type I collagen gene (COL1A1/COL1A2) of the fragments were sequenced to find the gene mutation, and bioinformatics software on the sequencing results were compared with the Genbank standard sequence analysis, the last four probands according to genetic test results, COL1A1/COL1A2 gene mutation of all the members were detected, sequenced, and analyzed by bioinformatics software.
Results
(1)Typing results of clinical diagnosis:Proband was diagnosed as typeⅣOI, his mother typeⅠOI; proband 2 typeⅠOI; proband 3 and his father, aunt TypeⅠOI; the proband 4 and his mother typeⅠOI.
(2) Genetic testing and sequencing:A c.2473 G>A mutation was found in the 36th exon of COL1A1 gene of the first propositus and the OI patients of the family, c.1821+1 G>A was found at the shearing site of the 26th intron of COL1A1 gene in the second propositus and c.697+2 C>T was found in the forth propositus at the ninth intron,then any COL1A1 or COL1A2 gene mutation was not found in the third propositus and the others.
Conclusions
(1)The genetic mutation of COL1A1 can lead to osteogenesis imperfecta, The genetic mutation of COL1A1 is one of the Chinese OI etiologic causes;
(2) For the Chinese people, there may be existence of other genetic changes can cause osteogenesis imperfecta,in addition to COL1A1/COL1A2 gene changes;
(3)The clinical manifestation is not only related with such gene changes and 01 genotype,but also with the genetic background,environment and others.
目的
本研究选取国内4个OI先证者家系,通过临床查体、病史问询、家系调查及基因突变的检测,明确各家系中患病个体的临床诊断分型,寻找基因突变位点,明确遗传方式,并探讨中国人群OI基因型与表型的关系,以丰富中国人群在这方面的资料,为该病的诊断预防及遗传咨询工作奠定一定的基础,并为将来可能的基因治疗提供理论依据。
方法
本研究选取2008年6月至2009年6月就诊于郑州大学第三附属医院门诊的河南省内的四个OI先证者,分别对其家系患病成员及部分健康成员进行临床体格检查、病史及家系调查,以收集临床资料,绘制不同家系的遗传图谱,确定各家系的遗传方式,根据sillence提出的经典分型标准对各家系中患病个体进行临床诊断分型；然后经患者本人及家属知情同意,并经医院伦理委员会同意批准,抽取家系中患病成员及部分健康成员的外周血液标本,提取血液标本的白细胞基因组DNA,应用PCR扩增的方法对四个先证者的COL1A1/COL1A2上所有的启动子,外显子及外显子-内含子区域进行基因扩增及基因突变检测,应用DNA直接测序法对4例先证者的Ⅰ型胶原基因(COL1A1/COL1A2基因)片段进行测序,然后应用生物信息学软件对测序结果与Genbank标准序列进行对比分析,以寻找基因突变的位点及形式,最后根据四个先证者的基因检测结果,分别对各家系其他成员的血液标本进行COL1A1/COL1A2基因的突变检测及测序,并应用生物信息学软件加以分析。
结果
(1)临床诊断分型结果：先证者一诊断为Ⅳ型OI,先证者一母亲诊断为Ⅰ型OI；先证者二诊断为Ⅰ型OI；先证者三及其父亲,姑姑均诊断为Ⅰ型OI；先证者四及其母亲均为Ⅰ型OI。
(2)基因检测及测序结果：在先证者一及其家系患病个体中检测到COL1A1基因上第36外显子c.2473位点G>A的突变,先证者二在COL1A1基因上第26内含子剪切位点处检测到c.1821+1位点G>A的突变,先证者四及其家系患病个体中检测到COL1A1基因上第9个内含子剪切位点处c.697-2位点C>T的突变,先证者三及四个家系中所有非患病成员个体均未检测到COL1A1/COL1A2基因上的突变。
结论
(1)COL1A1基因的改变可以导致成骨不全,也是引起中国人群成骨不全的原因之一；
(2)对于中国人群,除COL1A1/COL1A2基因的改变外,还可能具有能够引起成骨不全临床表型的其他基因改变的存在；
(3)成骨不全的临床表型不仅与基因型有关,还受到遗传背景、个人体质,人种差异、外周环境及其他因素的影响。
Osteogenesis imperfecta (OI) is a systemic hereditary connective tissue disease, which is divided into 7 types according to clinical manifestations and signs. A research shows that over 90% of patients exhibit OI type.Ⅰcollagen gene (COL1A1 and COL1A2) change, especially in the COL1A1 gene. The relationship between its genotype and phenotype keep uncertain yet, but the molecular genetic studies show that OI clinical manifestations are relative to gene mutations certainly, and some differences exist between ethnics or families, owning its features with private mutations frequently; the research on OI gene levels has become a hot topic at home and abroad. So far in abroad, more than a thousand species of type I collagen gene mutations lead to OI have been reported, but our research still stay at a low level, such as clinical or imaging reports et al.There is lack of the research on gene mutation.
Objective
To find gene mutation sites, determine genetic pattern and diagnose indefinitely by clinical physical examination, family and genetic testing,4 OI proband families will be selected in this research. We will explore the relationship between OI genotype and phenotype, enrich Chinese population data in this regard, and provide a theoretical basis for its diagnosis, prevention, genetic counseling and futuristic gene therapy.
Methods
The four out-OI proband from Henan Province who were seen the Third Affiliated Hospital of Zhengzhou University from June 2008 to September 2009 were selected in this research. Their family members and some members were given some clinical health examination, some clinical data such as medical history and family surveys were collected, genetic maps of different pedigrees were drawn, genetic methods were determined, individual type and clinical diagnosis were established according to sillence classic classification proposed standards; Then by the patient and the family agreed, and approved by the hospital ethics committee, affected family members and some healthy members of the peripheral blood were taken, genomic DNA of white blood cells were extracted, PCR amplification method of application of the four proband all those who COLlA1/COL1A2 promoter, exon and exon-intron region gene amplification and gene mutation, and then the DNA sequencing were applied for four cases of proband type I collagen gene (COL1A1/COL1A2) of the fragments were sequenced to find the gene mutation, and bioinformatics software on the sequencing results were compared with the Genbank standard sequence analysis, the last four probands according to genetic test results, COL1A1/COL1A2 gene mutation of all the members were detected, sequenced, and analyzed by bioinformatics software.
Results
(1)Typing results of clinical diagnosis:Proband was diagnosed as typeⅣOI, his mother typeⅠOI; proband 2 typeⅠOI; proband 3 and his father, aunt TypeⅠOI; the proband 4 and his mother typeⅠOI.
(2) Genetic testing and sequencing:A c.2473 G>A mutation was found in the 36th exon of COL1A1 gene of the first propositus and the OI patients of the family, c.1821+1 G>A was found at the shearing site of the 26th intron of COL1A1 gene in the second propositus and c.697+2 C>T was found in the forth propositus at the ninth intron,then any COL1A1 or COL1A2 gene mutation was not found in the third propositus and the others.
Conclusions
(1)The genetic mutation of COL1A1 can lead to osteogenesis imperfecta, The genetic mutation of COL1A1 is one of the Chinese OI etiologic causes;
(2) For the Chinese people, there may be existence of other genetic changes can cause osteogenesis imperfecta,in addition to COL1A1/COL1A2 gene changes;
(3)The clinical manifestation is not only related with such gene changes and 01 genotype,but also with the genetic background,environment and others.
引文
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[16]Glorieux FH, Rauch F, Plotkin H, et al. Bishop NJ Type V osteogenesis imperfecta:a new form of brittle bone disease[J].Bone Miner Res;2000,15(9):1650-1658
[17]Willing MC, Deschenes SP, Scott DA, et al. Osteogenesis imperfecta type I:molecular heterogeneity for COL1A1 null alleles of type I collagen[J].Hum Genet.1994,55(4): 638-647
[18]Korkko J, Ala-Kokko L, De Pacpe A, et al. Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning by conformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15 patients with osteogenesis imperfect type Ⅰ: identification of common sequences of null-allele mutations[J].Hum Genet.1998,62(3): 98-110
[19]Genovese C, Rowe D. Analysis of cytoplasmic and nuclear messenger RNA in fibroblasts from patients with type I osteogenesis imperfecta [J].Methods Enzymol.1987,145(1): 223-235
[20]Grossniklaus HE, Albert DM, Green WR,et al. Clear cell differentiation in choroidal melanoma, COMS report no.8 Collaborative Ocular Melanoma Study Group[J].Archives of ophthalmology; 1997,115(7):894-898
[21]Madenci E, Yilmaz K, Yilmaz M, et al. Alendronate treatment alendronate in osteogenesis imperfecta[J].Clin Rheumatol; 2006,12(5):53-60
[22]Glorieux FH, Ward LM, Rauch F, et al. Osteogenesis imperfecta type VI:a form of brittle bonedisease with a mineralization defect[J]. Bone Miner Res.2002,17(8):30-38
[23]Labuda M, Morissette J, Ward LM, et al. Osteogenesis imperfecta type Ⅶ maps to the short arm of chromosome 3.Bone;2002,31(1):19-25
[24]Plotkin H. Syndromes with congenital brittle bones[J].BMC Pediatr,2004,4(1):1-6
[25]Sillence DO, Senn A, Danks DM, et al. Genetic heterogeneity in osteogenesis imperfect[J]. Med Genet,1979,16(4):101-116
[26]Sykes B, Ogilvie D, Wordsworth P, et al. Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen lock COL1 A1 and COL1A2[J]. Hum Genet, 1990,46(2):293-307
[27]Byers PH. Osteogenesis Imperfecta:In Royce PM, Steinmann B (eds) Connective tissue and its heritable disorders:molecular, genetic and medical aspects[J].Wiley-Liss, New York.1993,3(1):17-50
[28]Glorieux FH, Rauch F, Plotkin H, et al. Type V Osteogenesis Imperfecta:A new form of brittle bone disease[J].Bone Min Res,2000,15(5):1650-1658
[29]Munns C, Rauch F, Travers R, et al. The effects of intravenous pamidronate treatment in infants with osteogenesis imperfecta:Clinical and histomor phometric outcome[J].Bone Miner Res;2005,20(7):1235-1243
[30]Horacio P, Francis H. Osteogenesis Imperfecta:Treatment & Medication[J].Drug Development Research,2004,2749(3):141-145
[31]Jezewski PA, Vieira AR,Nishimura C, et al. Complete sequencing Shows a role for MSX1 in non-syndromic cleft lip and palate[J].Med Gene,2003,40(2):399-407
[32]Horacio Plotkin, Frank Rauch, Nicholas J, et al. Pamidronate Treatment of Severe Osteogenesis Imperfecta in Children under 3 Years of Age [J].Endocrine Society;2000, 85(5):1846-1850
[33]Malfait F,Symoens S, De Backer J,et al.Three arginine to cysteine substitutions in the pro-alpha(Ⅰ)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rapture in early adulthood[J].Hum Murat,2007,28(4):387-395
[34]Starman BJ, Eyre D, Charbonneau H, et al. A novel mutation causes a perinatal form of osteogenesis imperfecta, An insertion in one alpha 1 collagen allele (COL1A1).Biol Chem; 1988,263(2):7855-7861
[35]Zhuang J, Tromp G, Kuivaniemi H, et al. Direct sequencing of PCR products derived from cDNAs for the proal and proa2 chains of type I procollagen as a screening method to detect mutations in patients with osteogenesis imperfecta[J].Hum Mutat,1996,7(2):89-99
[36]Pruchno CJ, Cohn DH, Wallis GA, et al. Osteogenesis imperfecta due to recurrent point mutations at CpG dinucleotides in the COL1A1 gene of type Ⅰ collagen[J].Hum Genet. 1991,87(1):33-40
[37]Suzuki Y. Jezewski PA, Machida J, et al. In a Vietnamese population, MSXI variants contribute to cleft lip and palate[J].Genet Med,2004,6(2):117-125
[38]夏欣一,崔英霞,杨滨,等.Ⅰ型胶原基因突变与成骨不全研究进展[J].中国优生与遗传杂志,2009,17(5)：8-13
[39]胡云秋,张浩,何进卫,等.成骨不全一家系1型胶原α1链基因新突变[J].上海医学,2009,32(7)：590-593
[40]Glorieux FH. Bisphosphonate therapy for severe osteogenesis imperfecta[J].Pediatr Endocrinol Metab;2000,13(2):989-992
[41]Zeitlin L, Rauch F, Plotkin H, et al. Height and weight development during long-term therapy with cyclical intravenous pamidronate in children and ado lescents with osteogenesis imperfecta types Ⅰ,Ⅲ and Ⅳ. Pediatrics; 2003,111(2):1032-1036
[42]Engelbert RH, Beemer FA, Vander Graaf Y, et al. Osteogenesis imperfecta in childhood: impairment and disability:a follow-up study[J].Arch Phys Med Rehabil,1999,80:896-903
[43]De Muynck S, Schollen E, Malthijs Getal. A novel MSXI mutalion in hypodontia[J]. Med Genet,2004,128(1):401-403
[44]Joseph R, Rebello G.The choice of intramedullary devices for the femur and tibia in osteogenesis imperfecta[J].Ped Orthop; 2005,14(5):311-319
[45]Morello R, Bertin TK, Chen YQ, et al. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive Osteogenesis Imperfecta. Cell.2006,127(20):291-304
[46]Rauch F, Lalic L, Roughley P, et al. Relationship Between Genotype and Skeletal Phenotype in Children and Adolescents With Osteogenesis Imperfecta[J].Bone Minder Res,2006,9(1):511-516
[47]Zacharin M, Bateman M. Pamidronate treatment of osteogenesis imperfecta lack of correlation between clinical severity, age at onset of treatment, predicted collagen mutation and trement response[J].Pediatr Endocrinol Metab.2002; 15(2):163-174
[48]Munns CF, Rauch F, Zeitin L, et al. Delayed osteotomy but not fractureheal inginpediatric osteogenesis imperfecta pationtsreceiving pamidronate[J],Bone Miner Res,2004,19(6): 1779-1786
[49]King D, Jar joura D, Mcewen HA, et al. Growth hormone in jections improve bone quality in a mouse model of osteogenesis imperfecta[J].Bone Miner Res,2005,20(1): 987-993
[50]Musgrave DS, Bosch P, Lee JY, et al. Ex vivo gene therapy to produce bone using different cell types[J].Clin Orthop Relat Res,2000,37(8):290-305
[51]Gotherstrom C, West A, Ringden O, et al. Difference in gene expression between human fetal liver and adult bone marrow mesenchymal stem cells [J].Transplantation,2005, 79(1):1607-1614
[52]Craig BL. Improvement of Bone in Patients with Osteogenesis Imperfecta Treated with Pamidronate Lessons from Biochemistry. Clinical Endocrinology & Metabolism;2003, 88(3):984-985
[53]Chamberlain JR,Wang PR,Ulrike S, et al. Genes Targting in Sten cells from indoviduals with osteogenesis imperfecta[J].Science,2004,2(303):1198-1201
Pamidronate Lessons from Biochemistry. Clinical Endocrinology & Metabolism; 2003,
88(3): 984-985
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[3]Craig BL. Improvement of Bone in Patients with Osteogenesis Imperfecta Treated with Pamidronate Lessons from Biochemistry. Clinical Endocrinology & Metabolism;2003, 88(3):984-985
[4]Lund A,Joensen F,Christensen E,et al.A novel arginine-to-cysteine substitution in the triple helical region of the alphal(I)collagen chain in a family with all esteogenesis imperfocta/Emem-Danles phenotype[J].Clin Cenet,2008,73(1):97-101
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[6]王卓,徐栋梁,陈峥,等.成骨不全一个新的Ⅰ型胶原α1链蛋白基因突变[J].中华医学杂志,2006,83(3)：170-173
[7]秦炜,何隽祥,施瑾,等.一成骨不全家系的COL1A1基因突变检测[J].遗传学报,2005,32(3)：248-252
[8]吴晓林,顾鸣敏,张一鸣,等.一例Ⅰ型成骨不全家系的基因定位及突变检测[J].上海交通大学学报(医学版),2007,27(6)：699-701
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[11]Plotkin H.Syndromes with congenital brittle bones[J].BMC Pediatr,2004,4(2):1-6
[12]宋今丹.医学细胞分子生物学.北京：人民卫生出版社,2003,63-64
[13]Labuda M, Morissette J, Ward LM, et al. Osteogenesis imperfecta type Ⅶ maps to the short arm of chromosome 3.Bone;2002,31(1):19-25
[14]Sykes B,Ogilvie D, Wordsworth P, et al. Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci:COL1A1 and COL1A2[J].Hum Genet. 1990,46(7):293-307
[15]Forlino A, Marini JC. Osteogenesis imperfecta:prospects for molecular therapeutics[J]. Mol Genet Metab.2000,71(5):225-32
[16]Glorieux FH, Rauch F, Plotkin H, et al. Bishop NJ Type V osteogenesis imperfecta:a new form of brittle bone disease[J].Bone Miner Res;2000,15(9):1650-1658
[17]Willing MC, Deschenes SP, Scott DA, et al. Osteogenesis imperfecta type I:molecular heterogeneity for COL1A1 null alleles of type I collagen[J].Hum Genet.1994,55(4): 638-647
[18]Korkko J, Ala-Kokko L, De Pacpe A, et al. Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning by conformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15 patients with osteogenesis imperfect type Ⅰ: identification of common sequences of null-allele mutations[J].Hum Genet.1998,62(3): 98-110
[19]Genovese C, Rowe D. Analysis of cytoplasmic and nuclear messenger RNA in fibroblasts from patients with type I osteogenesis imperfecta [J].Methods Enzymol.1987,145(1): 223-235
[20]Grossniklaus HE, Albert DM, Green WR,et al. Clear cell differentiation in choroidal melanoma, COMS report no.8 Collaborative Ocular Melanoma Study Group[J].Archives of ophthalmology; 1997,115(7):894-898
[21]Madenci E, Yilmaz K, Yilmaz M, et al. Alendronate treatment alendronate in osteogenesis imperfecta[J].Clin Rheumatol; 2006,12(5):53-60
[22]Glorieux FH, Ward LM, Rauch F, et al. Osteogenesis imperfecta type VI:a form of brittle bonedisease with a mineralization defect[J]. Bone Miner Res.2002,17(8):30-38
[23]Labuda M, Morissette J, Ward LM, et al. Osteogenesis imperfecta type Ⅶ maps to the short arm of chromosome 3.Bone;2002,31(1):19-25
[24]Plotkin H. Syndromes with congenital brittle bones[J].BMC Pediatr,2004,4(1):1-6
[25]Sillence DO, Senn A, Danks DM, et al. Genetic heterogeneity in osteogenesis imperfect[J]. Med Genet,1979,16(4):101-116
[26]Sykes B, Ogilvie D, Wordsworth P, et al. Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen lock COL1 A1 and COL1A2[J]. Hum Genet, 1990,46(2):293-307
[27]Byers PH. Osteogenesis Imperfecta:In Royce PM, Steinmann B (eds) Connective tissue and its heritable disorders:molecular, genetic and medical aspects[J].Wiley-Liss, New York.1993,3(1):17-50
[28]Glorieux FH, Rauch F, Plotkin H, et al. Type V Osteogenesis Imperfecta:A new form of brittle bone disease[J].Bone Min Res,2000,15(5):1650-1658
[29]Munns C, Rauch F, Travers R, et al. The effects of intravenous pamidronate treatment in infants with osteogenesis imperfecta:Clinical and histomor phometric outcome[J].Bone Miner Res;2005,20(7):1235-1243
[30]Horacio P, Francis H. Osteogenesis Imperfecta:Treatment & Medication[J].Drug Development Research,2004,2749(3):141-145
[31]Jezewski PA, Vieira AR,Nishimura C, et al. Complete sequencing Shows a role for MSX1 in non-syndromic cleft lip and palate[J].Med Gene,2003,40(2):399-407
[32]Horacio Plotkin, Frank Rauch, Nicholas J, et al. Pamidronate Treatment of Severe Osteogenesis Imperfecta in Children under 3 Years of Age [J].Endocrine Society;2000, 85(5):1846-1850
[33]Malfait F,Symoens S, De Backer J,et al.Three arginine to cysteine substitutions in the pro-alpha(Ⅰ)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rapture in early adulthood[J].Hum Murat,2007,28(4):387-395
[34]Starman BJ, Eyre D, Charbonneau H, et al. A novel mutation causes a perinatal form of osteogenesis imperfecta, An insertion in one alpha 1 collagen allele (COL1A1).Biol Chem; 1988,263(2):7855-7861
[35]Zhuang J, Tromp G, Kuivaniemi H, et al. Direct sequencing of PCR products derived from cDNAs for the proal and proa2 chains of type I procollagen as a screening method to detect mutations in patients with osteogenesis imperfecta[J].Hum Mutat,1996,7(2):89-99
[36]Pruchno CJ, Cohn DH, Wallis GA, et al. Osteogenesis imperfecta due to recurrent point mutations at CpG dinucleotides in the COL1A1 gene of type Ⅰ collagen[J].Hum Genet. 1991,87(1):33-40
[37]Suzuki Y. Jezewski PA, Machida J, et al. In a Vietnamese population, MSXI variants contribute to cleft lip and palate[J].Genet Med,2004,6(2):117-125
[38]夏欣一,崔英霞,杨滨,等.Ⅰ型胶原基因突变与成骨不全研究进展[J].中国优生与遗传杂志,2009,17(5)：8-13
[39]胡云秋,张浩,何进卫,等.成骨不全一家系1型胶原α1链基因新突变[J].上海医学,2009,32(7)：590-593
[40]Glorieux FH. Bisphosphonate therapy for severe osteogenesis imperfecta[J].Pediatr Endocrinol Metab;2000,13(2):989-992
[41]Zeitlin L, Rauch F, Plotkin H, et al. Height and weight development during long-term therapy with cyclical intravenous pamidronate in children and ado lescents with osteogenesis imperfecta types Ⅰ,Ⅲ and Ⅳ. Pediatrics; 2003,111(2):1032-1036
[42]Engelbert RH, Beemer FA, Vander Graaf Y, et al. Osteogenesis imperfecta in childhood: impairment and disability:a follow-up study[J].Arch Phys Med Rehabil,1999,80:896-903
[43]De Muynck S, Schollen E, Malthijs Getal. A novel MSXI mutalion in hypodontia[J]. Med Genet,2004,128(1):401-403
[44]Joseph R, Rebello G.The choice of intramedullary devices for the femur and tibia in osteogenesis imperfecta[J].Ped Orthop; 2005,14(5):311-319
[45]Morello R, Bertin TK, Chen YQ, et al. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive Osteogenesis Imperfecta. Cell.2006,127(20):291-304
[46]Rauch F, Lalic L, Roughley P, et al. Relationship Between Genotype and Skeletal Phenotype in Children and Adolescents With Osteogenesis Imperfecta[J].Bone Minder Res,2006,9(1):511-516
[47]Zacharin M, Bateman M. Pamidronate treatment of osteogenesis imperfecta lack of correlation between clinical severity, age at onset of treatment, predicted collagen mutation and trement response[J].Pediatr Endocrinol Metab.2002; 15(2):163-174
[48]Munns CF, Rauch F, Zeitin L, et al. Delayed osteotomy but not fractureheal inginpediatric osteogenesis imperfecta pationtsreceiving pamidronate[J],Bone Miner Res,2004,19(6): 1779-1786
[49]King D, Jar joura D, Mcewen HA, et al. Growth hormone in jections improve bone quality in a mouse model of osteogenesis imperfecta[J].Bone Miner Res,2005,20(1): 987-993
[50]Musgrave DS, Bosch P, Lee JY, et al. Ex vivo gene therapy to produce bone using different cell types[J].Clin Orthop Relat Res,2000,37(8):290-305
[51]Gotherstrom C, West A, Ringden O, et al. Difference in gene expression between human fetal liver and adult bone marrow mesenchymal stem cells [J].Transplantation,2005, 79(1):1607-1614
[52]Craig BL. Improvement of Bone in Patients with Osteogenesis Imperfecta Treated with Pamidronate Lessons from Biochemistry. Clinical Endocrinology & Metabolism;2003, 88(3):984-985
[53]Chamberlain JR,Wang PR,Ulrike S, et al. Genes Targting in Sten cells from indoviduals with osteogenesis imperfecta[J].Science,2004,2(303):1198-1201