Association of somatic mutations in Scribble gene with neural tube defects
TIAN Tian, ZHANG Ji, JIN Lei, WANG Linlin, REN Aiguo
Institute of Reproductive & Child Health; Ministry of Health Key Laboratory of Reproductive Health; Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
Abstract:Objective To screen mutations in SCRIB gene associated with neural tube defects (NTDs) in lesion tissue of the central nervous system, explore the source of mutations, and to identify whether they are somatic mutations.Methods DNA from the lesion and umbilical cord tissues of 28 fetuses/newborns with NTDs was sequenced by Ion Personal Genome Machine (PGM) and to screen somatic mutations. Sanger sequencing was used to detect the mutations in lesion ,umbilical cord, skin, heart, muscle, thymus and lung tissue. Validation in an independent sample set of 51 NTDs cases were performed.Results In all 28 NTDs cases, mutation of c.1931G>C was detected in the lesion tissue in one case and c.1265C>T was detected in another case through PGM sequencing; no mutations were detected in the umbilical cord tissue of corresponding cases, suggesting that c.1931G> C and c.1265C> T were somatic mutations. Mutation of c.1931G>C was detected in the skin, heart, muscle, thymus, and lung tissues in the case carrying the mutation; while mutation of C.1265C>T mutation was not detected in any tissues in the case carrying the mutation. The c.1931G>C mutation was not detected in the expanded sample, while c.1265C>T polymorphism was detected in the lesion and non-lesion tissues in 5 cases.Conclusion The mutations of SCRIB gene were associated with the occurrence of NTDs. The mutations may be inherited from parents, but also may be resulted from somatic mutation. Our study shed some light on the genetic mechanisms of NTDs development.
田甜,张继,靳蕾,王琳琳,任爱国. Scribble基因体细胞突变与神经管缺陷的关联研究[J]. 中国生育健康杂志, 2017, 28(5): 435-440.
TIAN Tian, ZHANG Ji, JIN Lei, WANG Linlin, REN Aiguo. Association of somatic mutations in Scribble gene with neural tube defects. Chinese Journal of Reproductive Health, 2017, 28(5): 435-440.
1 Copp AJ,Stanier P,Greene ND.Neural tube defects:recent advances,unsolved questions,and controversies.Lancet Neurol,2013,12:799-810. 2 Liu J,Zhang L,Li Z,et al.Prevalence and trend of neural tube defects in five counties in Shanxi province of Northern China,2000 to 2014.Birth Defects Res A Clin Mol Teratol,2016,106:267-274. 3 Williams J,Mai CT,Mulinare J,et al.Updated estimates of neural tube defects prevented by mandatory folic Acid fortification - United States,1995-2011.MMWR,2015,64:1-5. 4 Au KS,Ashley-Koch A,Northrup H.Epidemiologic and genetic aspects of spina bifida and other neural tube defects.Dev Disabil Res Rev,2010,16:6-15. 5 Juriloff DM,Harris MJ.A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects.Birth Defects Res A Clin Mol Teratol,2012,94:824-840. 6 Murdoch JN,Damrau C,Paudyal A,et al.Genetic interactions between planar cell polarity genes cause diverse neural tube defects in mice.Dis Model Mech,2014,7:1153-1163. 7 Robinson A,Escuin S,Doudney K,et al.Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis.Hum Mutat,2012,33:440-447. 8 Lei Y,Zhu H,Duhon C,et al.Mutations in planar cell polarity gene SCRIB are associated with spina bifida.PloS one,2013,8:e69262. 9 Erickson R.Somatic gene mutation and human disease other than cancer.Mutat Res,2003 543 :125-136. 10 Muotri AR,Chu VT,Marchetto MC,et al.Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition.Nature,2005,435:903-910. 11 Gollob MH,Jones DL,Krahn AD,et al.Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation.N Engl Med,2006,354:2677-2688. 12 Kury S,Airaud F,Piloquet P,et al.BAK1 gene variation and abdominal aortic aneurysms--results may have been prematurely overrated.Human mutation,2010,31:1174-1176;Author reply 1177-1178. 13 王媛媛 靳蕾,刘菊芬,等.神经管缺陷病理解剖结果与临床报告的对比分析.中国生育健康杂志,2015,26:207-210,215. 14 Knudson AG,Jr.Mutation and cancer:statistical study of retinoblastoma.PNAS,1971,68:820-823. 15 Adler PN.Planar signaling and morphogenesis in Drosophila.Dev Cell,2002,2(5):525-535. 16 Mlodzik M.Planar cell polarization:do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation? Trends Genet:TIG,2002,18:564-571. 17 Nola S,Sebbagh M,Marchetto S,et al.Scrib regulates PAK activity during the cell migration process.Hum Mol Genet,2008,17:3552-3565. 18 Montcouquiol M,Rachel RA,Lanford PJ,et al.Identification of Vangl2 and Scrb1 as planar polarity genes in mammals.Nature,2003,423:173-177. 19 Erickson RP.Somatic gene mutation and human disease other than cancer:An update.Mutat Res,2010,705 96-106. 20 Castro-Fernandez C,Arias M,Blanco-Arias P,et al.Targeted NGS meets expert clinical characterization:Efficient diagnosis of spastic paraplegia type 11.Appl Transl Genom,2015,5:33-36.