GTF2IRD1基因多态性与先天性小耳畸形发病的关系

Relationship between GTF2IRD1 Gene Polymorphism and the Pathogenesis of Congenital Microtia

冯涛;钱瑾;王悦;章庆国;

1:河北省张家口市妇幼保健院儿科

2:中国医学科学院整形外科医院

摘要
目的探讨GTF2IRD1基因突变是否与先天性小耳畸形有关。方法收集8岁左右小耳畸形患者328例(患者组)和30岁左右健康人群500例(对照组),分别采取静脉血2ml,采用候选基因关联研究的手段对GTF2IRD1基因在328例小耳畸形患者和500例对照者中进行比较分析,揭示同源盒基因GTF2IRD1与先天性小耳畸形之间的关系。结果通过飞行质谱法检测患者组与对照组GTF2IRD1基因中4个位点的基因型,关联研究在小儿畸形组发现了1个和小耳畸形显著关联的位点rs13244286[Bonferroni检验P=0.002 838 8,比值比(OR)=1.66],其位于GTF2IRD1基因编码HLH模体的关键序列附近。采用Impute2进行基因组填充后分析,又发现3个位点(rs13246861、rs34158545和rs73137122)与小耳畸形显著相关。结论本研究通过候选基因关联研究发现了4个可能的小耳畸形风险基因位点,证实GTF2IRD1基因与小耳畸形显著相关。
关键词
小耳畸形;GTF2IRD1基因;关联分析
基金项目(Foundation):
国家自然科学基金项目(81372085、81571924)
作者
冯涛;钱瑾;王悦;章庆国;
参考文献

1李威曼,王玲.出生缺陷儿监测资料回顾性分析[J].中国医学创新,2013,10:141.

2 Harris J,Kallén B,Robert E.The epidemiology of anotia and microtia[J].Journal of Medical Genetics,1996,33:809.

3 Mastroiacovo P,Corchia C,Botto LD,et al.Epidemiology and genetics of microtia-anotia:a registry based study on over one million births[J].Journal of Medical Genetics,1995,32:453.

4 Luquetti DV,Heike CL,Hing AV,et al.Microtia:epidemiology and genetics[J].American Journal of Medical Genetics Part A,2012,158:124.

5 Castilla EE,Lopez-Camelo JS,Campa1a H.Altitude as a risk factor for congenital anomalies[J].American Journal of Medical Genetics,1999,86:9.

6 Zhang Q,Zhang J,Yu P,et al.Environmental and genetic factors associated with congenital microtia:a case-control study in Jiangsu,China,2004to 2007[J].Plastic and Reconstructive Surgery,2009,124:1157.

7 Zhang YB,Hu J,Zhang J,et al.Genome-wide association study identifies multiple susceptibility loci for craniofacial microsomia[J].Nature Communications,2016,7:10605.

8 Mu1oz WA,Trainor PA.Neural crest cell evolution:how and when did a neural crest cell become a neural crest cell[J].Current Topics in Developmental Biology,2015,111:3.

9孙建军,赵晶.外耳及中耳的先天性畸形[J].中华耳鼻咽喉头颈外科杂志,2010,45:700.

10 Fogelgren B,Kuroyama MC,McBratney-Owen B,et al.Misexpression of Six2is associated with heritable frontonasal dysplasia and renal hypoplasia in 3H1Br mice[J].Developmental Dynamics,2008,237:1767.

11 Tekin M,Oztürkmen Akay H,Fitoz S,et al.Homozygous FGF3mutations result in congenital deafness with inner ear agenesis,microtia,and microdontia[J].Clinical Genetics,2008,73:554.

12 Alasti F,Sadeghi A,Sanati MH,et al.A mutation in HOXA2is responsible for autosomal-recessive microtia in an Iranian family[J].The American Journal of Human Genetics,2008,82:982.

13 Li X,Hu J,Zhang J,et al.Genome-wide linkage study suggests a susceptibility locus for isolated bilateral microtia on 4p15.32-4p16.2[J].PLoS One,2014,9:e101152.

14 Monks DC,Jahangir A,Shanske AL,et al.Mutational analysis of HOXA2and SIX2in a Bronx population with isolated microtia[J].International Journal of Pediatric Otorhinolaryngology,2010,74:878.

15 Hao S,Jin L,Li C,et al.Mutational analysis of GSC,HOXA2and PRKRA in 106Chinese patients with microtia[J].International Journal of Pediatric Otorhinolaryngology,2017,93:78.

16 Bayarsaihan D,Bitchevaia N,Enkhmandakh B,et al.Expression of BEN,a member of TFII-I family of transcription factors,during mouse pre-and postimplantation development[J].Gene Expression Patterns,2003,3:579.

17 Barrett JC,Fry B,Maller J,et al.Haploview:analysis and visualization of LD and haplotype maps[J].Bioinformatics,2004,21:263.

18 Xu S,Yin X,Li S,et al.Genomic dissection of population substructure of Han Chinese and its implication in association studies[J].The American Journal of Human Genetics,2009,85:762.

19 Howie BN,Donnelly P,Marchini J.A flexible and accurate genotype imputation method for the next generation of genome-wide association studies[J].PLoS Genetics,2009,5:e1000529.

20 Brown KK,Viana LM,Helwig CC,et al.HOXA 2haploinsufficiency in dominant bilateral microtia and hearing loss[J].Human Mutation,2013,34:1347.

21 Alsmadi O,Meyer BF,Alkuraya F,et al.Syndromic congenital sensorineural deafness,microtia and microdontia resulting from a novel homoallelic mutation in fibroblast growth factor 3(FGF3)[J].European Journal of Human Genetics,2009,17:14.

22 Gillespie RL,Urquhart J,Lovell SC,et al.Abrogation of HMX1function causes rare oculoauricular syndrome associated with congenital cataract,anterior segment dysgenesis,and retinal dystrophy[J].Investigative Ophthalmology&Visual Science,2015,56:883.

23郝少娟,金蕾,李辰龙,等.先天性小耳畸形候选致病基因的筛选[J].中国眼耳鼻喉科杂志,2017,17:011.

24 Tassabehji M,Hammond P,Karmiloff-Smith A,et al.GTF2IRD1in craniofacial development of humans and mice[J].Science,2005,310:1184.

25 Canales CP,Wong ACY,Gunning PW,et al.The role of GTF2IRD1in the auditory pathology of Williams-Beuren Syndrome[J].European Journal of Human Genetics,2015,23:774.

26 Howard ML,Palmer SJ,Taylor KM,et al.Mutation of Gtf2ird1from the Williams-Beuren syndrome critical region results in facial dysplasia,motor dysfunction,and altered vocalisations[J].Neurobiology of Disease,2012,45:913.

27 Enkhmandakh B,Makeyev AV,Erdenechimeg L,et al.Essential functions of the Williams-Beuren syndrome-associated TFII-I genes in embryonic development[J].Proceedings of the National Academy of Sciences,2009,106:181.

28 Palmer SJ,Santucci N,Widagdo J,et al.Negative autoregulation of GTF2IRD1in Williams-Beuren syndrome via a novel DNA binding mechanism[J].Journal of Biological Chemistry,2010,285:4715.

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冯涛钱瑾王悦章庆国