FMR1基因CGG重复序列多态性与不明原因早期自然流产的相关性研究
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摘要
目的探讨脆性X智力障碍基因1(FMR1)基因CGG重复序列与不明原因早期自然流产发病机制的相关性。方法收集2015年5月1日至2018年4月1日在北京妇产医院计划生育科就诊的难免流产或需行清宫操作的2 000例患者为自然流产组;同期在北京妇产医院产科就诊的1 480例顺利分娩女性为对照组。两组患者均于孕早期或孕中期抽取外周血,提取基因组DNA,应用FMR1基因Amplide X检测技术进行FMR1基因CGG重复序列数检测。比较两组CGG重复序列情况并加以分析。结果 (1)所有对象的FMR1基因检测未检出全突变病例;自然流产组中CGG重复最大频率等位基因n=30(32.95%),其后依次是29(31.15%)、36(15.60%)、31(5.85%);对照组CGG重复最大频率等位基因为n=30(33.24%),其后依次为29(25.47%)、36(14.73%)、31(8.38%)。自然流产组及对照组CGG重复位点均数比较无显著性差异[(29.33±5.19)vs.(28.73±6.37)](P>0.05)。(2)自然流产组FMR1基因中间型携带率为1∶222,对照组1∶247,组间比较无显著性差异(P>0.05)。自然流产组的脆性X综合征前突变携带频率(1∶400)显著高于对照组(1∶740)(P<0.05)。结论 FMR1基因CGG重复序列前突变与不明原因早期自然流产可能存在相关性。
Objective:To investigate the relationship between the CGG repeat of the fragile X mental retardation gene 1(FMR1)gene and the pathogenesis of unexplained early spontaneous abortion.Methods:Two thousands patients with spontaneous abortion or need clearing uterine surgery were collected as spontaneous abortion group at the Family Planning Department of Beijing Maternity Hospital from May 1,2015 to April 1,2018.In the same period,1 480 women who had successfully delivered to the obstetrics department of Beijing Maternity Hospital were as control group.Peripheral blood was extracted and genomic DNA was extracted.The Amplide XTM gene detection technique was used to detect CGG repeat polymorphism of FMR1 gene.The results were compared between the two groups.Results:The full mutation of FMR1 gene was not detected in all samples.The maximum frequency allele of FMR1-CGG repeats was 30(32.95%),followed by 29(31.15%),36(15.60%)and 31(5.85%)in the spontaneous abortion group.The maximum frequency allele of FMR1-CGG repeats was 30(33.24%),followed by 29(25.47%),36(14.73%),31(8.38%)in the control group.The average number of CGG repetitions was not significantly different between spontaneous abortion group and control group[(29.33±5.19)vs.(28.73±6.37)](P>0.05).The intermediate carrying rate of FMR1 gene in the spontaneous abortion group and in the control group was 1∶222 and 1∶247 respectively,and the difference was not significant(P>0.05).The frequency of premutation(PM)of fragile X syndrome(1∶400)in spontaneous abortion group was significantly higher than that in the control group(1∶740)(P<0.05).Conclusions:The premutation of FMR1 gene maybe related with unexplained early spontaneous abortion.
Objective:To investigate the relationship between the CGG repeat of the fragile X mental retardation gene 1(FMR1)gene and the pathogenesis of unexplained early spontaneous abortion.Methods:Two thousands patients with spontaneous abortion or need clearing uterine surgery were collected as spontaneous abortion group at the Family Planning Department of Beijing Maternity Hospital from May 1,2015 to April 1,2018.In the same period,1 480 women who had successfully delivered to the obstetrics department of Beijing Maternity Hospital were as control group.Peripheral blood was extracted and genomic DNA was extracted.The Amplide XTM gene detection technique was used to detect CGG repeat polymorphism of FMR1 gene.The results were compared between the two groups.Results:The full mutation of FMR1 gene was not detected in all samples.The maximum frequency allele of FMR1-CGG repeats was 30(32.95%),followed by 29(31.15%),36(15.60%)and 31(5.85%)in the spontaneous abortion group.The maximum frequency allele of FMR1-CGG repeats was 30(33.24%),followed by 29(25.47%),36(14.73%),31(8.38%)in the control group.The average number of CGG repetitions was not significantly different between spontaneous abortion group and control group[(29.33±5.19)vs.(28.73±6.37)](P>0.05).The intermediate carrying rate of FMR1 gene in the spontaneous abortion group and in the control group was 1∶222 and 1∶247 respectively,and the difference was not significant(P>0.05).The frequency of premutation(PM)of fragile X syndrome(1∶400)in spontaneous abortion group was significantly higher than that in the control group(1∶740)(P<0.05).Conclusions:The premutation of FMR1 gene maybe related with unexplained early spontaneous abortion.
引文
[1] Massalska D,Zimowski JG,Bijok J,et al.First trimester pregnancy loss:Clinical implications of genetic testing[J].J Obstet Gynaecol Res,2017,43:23-29.
[2]陈兰婷,李大金,王凌.复发性流产的遗传学相关因素研究进展[J].生殖医学杂志,2017,26:1158-1162.
[3] Suzumori N,Sugiura-Ogasawara M.Genetic factors as a cause of miscarriage[J].Curr Med Chem,2010,17:3431-3437.
[4] Verkerk AJ,Pieretti M,Suteliffe JS,el a1.Identification of a gene(FMR-1)containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome[J].Cell,1991,65:905-914.
[5] Kronquist KE,Sherman SL,Spector EB.Clinical significance of tri-nucleotide repeats in Fragile X testing:a clarification of American College of Medical Genetics guidelines[J].Genet Med,2008,10:845-847.
[6] Nolin SL,Lewis FA 3rd,Ye LL,et al.Familial transmission of the FMR1CGG repeat[J].Am J Hum Genet,1996,59:1252-1261.
[7] Ye Y,Lan X,Cong J,et al.Analysis of CGG repeats in FMR1in Chinese women with idiopathic premature ovarian failure[J/OL].Reprod Biomed Online,2014,29:382-387.
[8] Nolin SL,Sah S,Glicksman A,et al.Fragile X AGG analysis provides new risk predictions for 45-69repeat alleles[J].Am J Med Genet A,2013,161A:771-778.
[9]张有成,王和.中国西南一城市智力低下人群中脆性X综合征发病率调查[J].遵义医学院学报,2016,39:223-228.
[10]巫向前,江忠仪,殷常红,等.正常人群中FMR-1等位基因的调查及分析[J].上海医学,2000,23:88-90.
[11]刘帆,杨楠,黄新林,等.乌鲁木齐市汉族育龄女性FMR1基因(CGG)n序列变异检测分析[J].中国优生与遗传杂志,2017,25:13-15.
[12]马云,何淑雅,李斌元,等.不同民族人群FMR1基因CGG重复序列检测与分析[J].国际遗传学杂志,2007,30:325-328.
[13] Lu CL,Li R,Chen XN,et al.The‘normal’range of FMR1triple CGG repeats may be associated with primary ovarian insufficiency in China[J/OL].Reprod Biomed Online,2017,34:175-180.
[14] Tassone F,Iong KP,Tong TH,et al.FMR1CGG allele size and prevalence ascertained through newborn screening in the United States[J].Genome Med,2012,4:100.
[15] Coffee B.Commentary on population screening for fragile X syndrome[J].Genet Med,2010,12:411-412.
[16] Jang JH,Lee K,Cho EH,et al.Frequency of FMR1premutation carriers and rate of expansion to full mutation in a retrospective diagnostic FMR1 Korean sample[J].Clin Genet,2014,85:441-445.
[17] Tzeng CC,Tsai LP,Hwu WL,et al.Prevalence of the FMR1mutation in Taiwan assessed by large-scale screening of newborn boys and analysis of DXS548-FRAXACI haplotype[J].Am J Med Genet A,2005,133A:37-43.
[18] Voorhuis M,Onland-Moret NC,Fauser BC,et al.The association of CGG repeats in the FMR1gene and timing of natural menopause[J].Hum Reprod,2013,28:496-501.
[19] Lledo B,Guerrero J,Ortiz JA,et al.Intermediate and normal sized CGG repeat on the FMR1gene does not negatively affect donor ovarian response[J].Hum Reprod,2012,27:609-614.
[20] Sherman SL.Premature ovarian failure in the fragile X syndrome[J].Am J Med Genet,2000,97:189-194.
[21] Sullivan AK,Marcus M,Epstein MP,et al.Association of FMR1 repeat size with ovarian dysfunction[J]. Hum Reprod,2005,20:402-412.
[22] Bretherick KL,Fluker MR,Robinson WP.FMR1repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure[J].Hum Genet,2005,117:376-382.
[23] Kline J,Kinney A,Brown S,et al.Trisomic pregnancy and intermediate CGG repeat length at the FMR1locus[J].Hum Reprod,2012,27:2224-2232.
[24] Kline JK,Kinney AM,Levin B,et al.Trisomic pregnancy and elevated FSH:implications for the oocyte pool hypothesis[J].Hum Reprod,2011,26:1537-1550.
[25] Strom CM,Crossley B,Redman JB,et al.Molecular testing for Fragile X Syndrome:lessons learned from 119,232tests performed in a clinical laboratory[J].Genet Med,2007,9:46-51.
[26] Yrigollen CM,Durbin-Johnson B,Gane L,et al.AGG interruptions within the maternal FMR1gene reduce the risk of offspring with fragile X syndrome[J].Genet Med,2012,14:729-736.
[27]叶玉琴,吴洁.卵巢功能早衰与脆性X智力低下1基因的关系[J].生殖医学杂志,2013,22:551-554.
[28] Martin JR,Arici A.Fragile X and reproduction[J].Curr Opin Obstet Gynecol,2008,20:216-220.
[29] Saul RA,Friez M,Eaves K,et al.Fragile X syndrome detection in newborns-pilot study[J].Genet Med,2008,10:714-719.
[30] Hill MK,Archibald AD,Cohen J,et al.A systematic review of population screening for fragile X syndrome[J].Genet Med,2010,12:396-410.
[2]陈兰婷,李大金,王凌.复发性流产的遗传学相关因素研究进展[J].生殖医学杂志,2017,26:1158-1162.
[3] Suzumori N,Sugiura-Ogasawara M.Genetic factors as a cause of miscarriage[J].Curr Med Chem,2010,17:3431-3437.
[4] Verkerk AJ,Pieretti M,Suteliffe JS,el a1.Identification of a gene(FMR-1)containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome[J].Cell,1991,65:905-914.
[5] Kronquist KE,Sherman SL,Spector EB.Clinical significance of tri-nucleotide repeats in Fragile X testing:a clarification of American College of Medical Genetics guidelines[J].Genet Med,2008,10:845-847.
[6] Nolin SL,Lewis FA 3rd,Ye LL,et al.Familial transmission of the FMR1CGG repeat[J].Am J Hum Genet,1996,59:1252-1261.
[7] Ye Y,Lan X,Cong J,et al.Analysis of CGG repeats in FMR1in Chinese women with idiopathic premature ovarian failure[J/OL].Reprod Biomed Online,2014,29:382-387.
[8] Nolin SL,Sah S,Glicksman A,et al.Fragile X AGG analysis provides new risk predictions for 45-69repeat alleles[J].Am J Med Genet A,2013,161A:771-778.
[9]张有成,王和.中国西南一城市智力低下人群中脆性X综合征发病率调查[J].遵义医学院学报,2016,39:223-228.
[10]巫向前,江忠仪,殷常红,等.正常人群中FMR-1等位基因的调查及分析[J].上海医学,2000,23:88-90.
[11]刘帆,杨楠,黄新林,等.乌鲁木齐市汉族育龄女性FMR1基因(CGG)n序列变异检测分析[J].中国优生与遗传杂志,2017,25:13-15.
[12]马云,何淑雅,李斌元,等.不同民族人群FMR1基因CGG重复序列检测与分析[J].国际遗传学杂志,2007,30:325-328.
[13] Lu CL,Li R,Chen XN,et al.The‘normal’range of FMR1triple CGG repeats may be associated with primary ovarian insufficiency in China[J/OL].Reprod Biomed Online,2017,34:175-180.
[14] Tassone F,Iong KP,Tong TH,et al.FMR1CGG allele size and prevalence ascertained through newborn screening in the United States[J].Genome Med,2012,4:100.
[15] Coffee B.Commentary on population screening for fragile X syndrome[J].Genet Med,2010,12:411-412.
[16] Jang JH,Lee K,Cho EH,et al.Frequency of FMR1premutation carriers and rate of expansion to full mutation in a retrospective diagnostic FMR1 Korean sample[J].Clin Genet,2014,85:441-445.
[17] Tzeng CC,Tsai LP,Hwu WL,et al.Prevalence of the FMR1mutation in Taiwan assessed by large-scale screening of newborn boys and analysis of DXS548-FRAXACI haplotype[J].Am J Med Genet A,2005,133A:37-43.
[18] Voorhuis M,Onland-Moret NC,Fauser BC,et al.The association of CGG repeats in the FMR1gene and timing of natural menopause[J].Hum Reprod,2013,28:496-501.
[19] Lledo B,Guerrero J,Ortiz JA,et al.Intermediate and normal sized CGG repeat on the FMR1gene does not negatively affect donor ovarian response[J].Hum Reprod,2012,27:609-614.
[20] Sherman SL.Premature ovarian failure in the fragile X syndrome[J].Am J Med Genet,2000,97:189-194.
[21] Sullivan AK,Marcus M,Epstein MP,et al.Association of FMR1 repeat size with ovarian dysfunction[J]. Hum Reprod,2005,20:402-412.
[22] Bretherick KL,Fluker MR,Robinson WP.FMR1repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure[J].Hum Genet,2005,117:376-382.
[23] Kline J,Kinney A,Brown S,et al.Trisomic pregnancy and intermediate CGG repeat length at the FMR1locus[J].Hum Reprod,2012,27:2224-2232.
[24] Kline JK,Kinney AM,Levin B,et al.Trisomic pregnancy and elevated FSH:implications for the oocyte pool hypothesis[J].Hum Reprod,2011,26:1537-1550.
[25] Strom CM,Crossley B,Redman JB,et al.Molecular testing for Fragile X Syndrome:lessons learned from 119,232tests performed in a clinical laboratory[J].Genet Med,2007,9:46-51.
[26] Yrigollen CM,Durbin-Johnson B,Gane L,et al.AGG interruptions within the maternal FMR1gene reduce the risk of offspring with fragile X syndrome[J].Genet Med,2012,14:729-736.
[27]叶玉琴,吴洁.卵巢功能早衰与脆性X智力低下1基因的关系[J].生殖医学杂志,2013,22:551-554.
[28] Martin JR,Arici A.Fragile X and reproduction[J].Curr Opin Obstet Gynecol,2008,20:216-220.
[29] Saul RA,Friez M,Eaves K,et al.Fragile X syndrome detection in newborns-pilot study[J].Genet Med,2008,10:714-719.
[30] Hill MK,Archibald AD,Cohen J,et al.A systematic review of population screening for fragile X syndrome[J].Genet Med,2010,12:396-410.