Seminars in Pediatric Neurology
Volume 16, Issue 3 , Pages 101-110 , September 2009

Genetic Basis of Neural Tube Defects

  • Alexander G. Bassuk, MD, PhD

      Affiliations

    • Department of Pediatrics, University of Iowa, Iowa City, IA
  • ,
  • Zoha Kibar, PhD

      Affiliations

    • Department of Obstetrics and Gynecology, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada
    • Corresponding Author InformationAddress reprint requests to Zoha Kibar, PhD, CHU Sainte-Justine Research Center, 3175 Cote-Ste-Catherine, Montreal, QC, H3T 1C5 Canada

References 

  1. Kibar Z, Capra V, Gros P. Toward understanding the genetic basis of neural tube defects. Clin Genet. 2007;71:295–310
  2. Botto LD, Moore CA, Khoury MJ, et al. Neural-tube defects. N Engl J Med. 1999;341:1509–1519
  3. Rossi A, Biancheri R, Cama A, et al. Imaging in spine and spinal cord malformations. Eur J Radiol. 2004;50:177–200
  4. Frey L, Hauser WA. Epidemiology of neural tube defects. Epilepsia. 2003;44(suppl 3):4–13
  5. Mitchell LE. Epidemiology of neural tube defects. Am J Med Genet C Semin Med Genet. 2005;135C:88–94
  6. Greene ND, Copp AJ. Development of the vertebrate central nervous system: Formation of the neural tube. Prenat Diagn. 2009;29:303–311
  7. Bainter JJ, Boos A, Kroll KL. Neural induction takes a transcriptional twist. Dev Dyn. 2001;222:315–327
  8. De Robertis EM, Kuroda H. Dorsal-ventral patterning and neural induction in Xenopus embryos. Annu Rev Cell Dev Biol. 2004;20:285–308
  9. Stern CD. Neural induction: 10 Years on since the “default model”. Curr Opin Cell Biol. 2006;18:692–697
  10. Wallingford JB, Fraser SE, Harland RM. Convergent extension: The molecular control of polarized cell movement during embryonic development. Dev Cell. 2002;2:695–706
  11. Keller R, Shook D, Skoglund P. The forces that shape embryos: Physical aspects of convergent extension by cell intercalation. Phys Biol. 2008;5:15007
  12. Simons M, Mlodzik M. Planar cell polarity signaling: from fly development to human disease. Annu Rev Genet. 2008;42:517–540
  13. Hui CC, Joyner AL. A mouse model of Greig cephalopolysyndactyly syndrome: The extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nat Genet. 1993;3:241–246
  14. Goodrich LV, Milenkovic L, Higgins KM, et al. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science. 1997;277:1109–1113
  15. Huang Y, Roelink H, McKnight GS. Protein kinase A deficiency causes axially localized neural tube defects in mice. J Biol Chem. 2002;277:19889–19896
  16. Ybot-Gonzalez P, Cogram P, Gerrelli D, et al. Sonic hedgehog and the molecular regulation of mouse neural tube closure. Development. 2002;129:2507–2517
  17. Wallingford JB. Neural tube closure and neural tube defects: Studies in animal models reveal known knowns and known unknowns. Am J Med Genet C Semin Med Genet. 2005;135C:59–68
  18. Brouns MR, Matheson SF, Hu KQ, et al. The adhesion signaling molecule p190 rhoGAP is required for morphogenetic processes in neural development. Development. 2000;127:4891–4903
  19. Hildebrand JD, Soriano P. Shroom, a PDZ domain-containing actin-binding protein, is required for neural tube morphogenesis in mice. Cell. 1999;99:485–497
  20. Haigo SL, Hildebrand JD, Harland RM, et al. Shroom induces apical constriction and is required for hingepoint formation during neural tube closure. Curr Biol. 2003;13:2125–2137
  21. Holmberg J, Clarke DL, Frisen J. Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature. 2000;408:203–206
  22. Abdul-Aziz NM, Turmaine M, Greene ND, et al. EphrinA-EphA receptor interactions in mouse spinal neurulation: Implications for neural fold fusion. Int J Dev Biol. 2009;53:559–568
  23. Mellitzer G, Xu Q, Wilkinson DG. Control of cell behaviour by signaling through Eph receptors and ephrins. Curr Opin Neurobiol. 2000;10:400–408
  24. Juriloff DM, Harris MJ, Tom C, et al. Normal mouse strains differ in the site of initiation of closure of the cranial neural tube. Teratology. 1991;44:225–233
  25. Fleming A, Copp AJ. A genetic risk factor for mouse neural tube defects: Defining the embryonic basis. Hum Mol Genet. 2000;9:575–581
  26. Van AMI, Kalousek DK, Chernoff GF, et al. Evidence for multi-site closure of the neural tube in humans. Am J Med Genet. 1993;47:723–743
  27. Nakatsu T, Uwabe C, Shiota K. Neural tube closure in humans initiates at multiple sites: Evidence from human embryos and implications for the pathogenesis of neural tube defects. Anat Embryol (Berl). 2000;201:455–466
  28. O'Rahilly R, Muller F. The two sites of fusion of the neural folds and the two neuropores in the human embryo. Teratology. 2002;65:162–170
  29. Catala M. Genetic control of caudal development. Clin Genet. 2002;61:89–96
  30. Bassuk AG, Craig D, Jalali A, et al. The genetics of tethered cord syndrome. Am J Med Genet A. 2005;132:450–453
  31. Lynch SA. Non-multifactorial neural tube defects. Am J Med Genet C Semin Med Genet. 2005;135C:69–76
  32. Racial/ethnic differences in the birth prevalence of spinal bifida—United States, 1995-2005. MMWR. Morb Mortal Wkly Rep. 2009;57:1409–1413
  33. Manning SM, Jennings R, Madsen JR. Pathophysiology, prevention, and potential treatment of neural tube defects. Ment Retard Dev Disabil Res Rev. 2000;6:6–14
  34. Detrait ER, George TM, Etchevers HC, et al. Human neural tube defects: Developmental biology, epidemiology, and genetics. Neurotoxicol Teratol. 2005;27:515–524
  35. Byrne J, Carolan S. Adverse reproductive outcomes among pregnancies of aunts and (spouses of) uncles in Irish families with neural tube defects. Am J Med Genet A. 2006;140:52–61
  36. Deak KL, Siegel DG, George TM, et al. Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects. Birth Defects Res A Clin Mol Teratol. 2008;82:662–669
  37. Rampersaud E, Bassuk AG, Enterline DS, et al. Whole genomewide linkage screen for neural tube defects reveals regions of interest on chromosomes 7 and 10. J Med Genet. 2005;42:940–946
  38. Stamm DS, Rampersaud E, Slifer SH, et al. High-density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1-pter and 2q33.1-q35. Birth Defects Res A Clin Mol Teratol. 2006;76:499–505
  39. MRC, Vitamin Study Research Group. Prevention of neural tube defects: Results of the Medical Research Council Vitamin study. Lancet. 1991;338:131–137
  40. Beaudin AE, Stover PJ. Insights into metabolic mechanisms underlying folate-responsive neural tube defects: A minireview. Birth Defects Res A Clin Mol Teratol. 2009;85:274–284
  41. van der Linden IJ, Afman LA, Heil SG, et al. Genetic variation in genes of folate metabolism and neural-tube defect risk. Proc Nutr Soc. 2006;65:204–215
  42. Piedrahita JA, Oetama B, Bennett GD, et al. Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. Nat Genet. 1999;23:228–232
  43. Rothenberg SP, da Costa MP, Sequeira JM, et al. Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect. N Engl J Med. 2004;350:134–142
  44. Boyles AL, Billups AV, Deak KL, et al. Neural tube defects and folate pathway genes: Family-based association tests of gene-gene and gene-environment interactions. Environ Health Perspect. 2006;114:1547–1552
  45. Franke B, Vermeulen SH, Steegers-Theunissen RP, et al. An association study of 45 folate-related genes in spinal bifida: Involvement of cubilin (CUBN) and tRNA aspartic acid methyltransferase 1 (TRDMT1). Birth Defects Res A Clin Mol Teratol. 2009;85:216–226
  46. De Marco P, Calevo MG, Moroni A, et al. Reduced folate carrier polymorphism (80A—>G) and neural tube defects. Eur J Hum Genet. 2003;11:245–252
  47. O'Leary VB, Pangilinan F, Cox C, et al. Reduced folate carrier polymorphisms and neural tube defect risk. Mol Genet Metab. 2006;87:364–369
  48. Blom HJ, Shaw GM, den Heijer M, et al. Neural tube defects and folate: Case far from closed. Nat Rev Neurosci. 2006;7:724–731
  49. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A HuGE review. Am J Epidemiol. 2000;151:862–877
  50. van der Put NM, Eskes TK, Blom HJ. Is the common 677C—>T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? (A meta-analysis). QJM. 1997;90:111–115
  51. van der Put NM, Gabreels F, Stevens EM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects?. Am J Hum Genet. 1998;62:1044–1051
  52. Chen Z, Karaplis AC, Ackerman SL, et al. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet. 2001;10:433–443
  53. Li D, Pickell L, Liu Y, et al. Maternal methylenetetrahydrofolate reductase deficiency and low dietary folate lead to adverse reproductive outcomes and congenital heart defects in mice. Am J Clin Nutr. 2005;82:188–195
  54. Swanson DA, Liu ML, Baker PJ, et al. Targeted disruption of the methionine synthase gene in mice. Mol Cell Biol. 2001;21:1058–1065
  55. Elmore CL, Wu X, Leclerc D, et al. Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase. Mol Genet Metab. 2007;91:85–97
  56. Hol FA, van der Put NM, Geurds MP, et al. Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects. Clin Genet. 1998;53:119–125
  57. Brody LC, Conley M, Cox C, et al. A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: Report of the Birth Defects Research Group. Am J Hum Genet. 2002;71:1207–1215
  58. De Marco P, Merello E, Calevo MG, et al. Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G > A polymorphism for neural tube defect risk. J Hum Genet. 2006;51:98–103
  59. Beaudin AE, Stover PJ. Folate-mediated one-carbon metabolism and neural tube defects: Balancing genome synthesis and gene expression. Birth Defects Res C Embryo Today. 2007;81:183–203
  60. Volcik KA, Shaw GM, Lammer EJ, et al. Evaluation of infant methylenetetrahydrofolate reductase genotype, maternal vitamin use, and risk of high versus low level spinal bifida defects. Birth Defects Res A Clin Mol Teratol. 2003;67:154–157
  61. Shaw GM, Lammer EJ, Zhu H, et al. Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spinal bifida. Am J Med Genet. 2002;108:1–6
  62. Zohn IE, Sarkar AA. Modeling neural tube defects in the mouse. Curr Top Dev Biol. 2008;84:1–35
  63. Harris MJ, Juriloff DM. Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects. Birth Defects Res A Clin Mol Teratol. 2007;79:187–210
  64. Deak KL, Dickerson ME, Linney E, et al. Analysis of ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2 in human neural tube defects suggests a possible association with alleles in ALDH1A2. Birth Defects Res A Clin Mol Teratol. 2005;73:868–875
  65. Rat E, Billaut-Laden I, Allorge D, et al. Evidence for a functional genetic polymorphism of the human retinoic acid-metabolizing enzyme CYP26A1, an enzyme that may be involved in spinal bifida. Birth Defects Res A Clin Mol Teratol. 2006;76:491–498
  66. Stegmann K, Boecker J, Richter B, et al. A screen for mutations in human homologues of mice exencephaly genes Tfap2alpha and Msx2 in patients with neural tube defects. Teratology. 2001;63:167–175
  67. Deak KL, Boyles AL, Etchevers HC, et al. SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects. Hum Genet. 2005;117:133–142
  68. Hol FA, Geurds MP, Chatkupt S, et al. PAX genes and human neural tube defects: An amino acid substitution in Pax1 in a patient with spinal bifida. J Med Genet. 1996;33:655–660
  69. Volcik KA, Blanton SH, Kruzel MC, et al. Testing for genetic associations with the PAX gene family in a spinal bifida population. Am J Med Genet. 2002;110:195–202
  70. Hol FA, Hamel BC, Geurds MP, et al. A frameshift mutation in the gene for Pax3 in a girl with spinal bifida and mild signs of Waardenburg syndrome. J Med Genet. 1995;32:52–56
  71. Lu W, Zhu H, Wen S, et al. Screening for novel Pax3 polymorphisms and risks of spinal bifida. Birth Defects Res A Clin Mol Teratol. 2007;79:45–49
  72. Zhu H, Wicker NJ, Volcik K, et al. Promoter haplotype combinations for the human PDGFRA gene are associated with risk of neural tube defects. Mol Genet Metab. 2004;81:127–132
  73. Au KS, Northrup H, Kirkpatrick TJ, et al. Promoter genotype of the platelet-derived growth factor receptor-alpha gene shows population stratification but not association with spinal bifida meningomyelocele. Am J Med Genet A. 2005;139:194–198
  74. Joosten PH, Toepoel M, Mariman EC, et al. Promoter haplotype combinations of the platelet-derived growth factor alpha-receptor gene predispose to human neural tube defects. Nat Genet. 2001;27:215–217
  75. Zhu H, Lu W, Laurent C, et al. Genes encoding catalytic subunits of protein kinase A and risk of spinal bifida. Birth Defects Res A Clin Mol Teratol. 2005;73:591–596
  76. Stegmann K, Boecker J, Kosan C, et al. Human transcription factor SLUG: Mutation analysis in patients with neural tube defects and identification of a missense mutation (D119E) in the slug subfamily-defining region. Mutat Res. 1999;406:63–69
  77. Morrison K, Papapetrou C, Hol FA, et al. Susceptibility to spinal bifida; an association study of five candidate genes. Ann Hum Genet. 1998;62:379–396
  78. Trembath D, Sherbondy AL, Vandyke DC, et al. Analysis of select folate pathway genes, Pax3, and human T in a midwestern neural tube defect population. Teratology. 1999;59:331–341
  79. Kibar Z, Torban E, McDearmid JR, et al. Mutations in VANGL1 associated with neural-tube defects. N Engl J Med. 2007;356:1432–1437
  80. Kibar Z, Bosoi CM, Kooistra M, et al. Novel mutations in VANGL1 in Neural Tube Defects. Hum Mutat. 2009;30:E706–E715
  81. Klootwijk R, Groenen P, Schijvenaars M, et al. Genetic variants in ZIC1, ZIC2, and ZIC3 are not major risk factors for neural tube defects in humans. Am J Med Genet A. 2004;124A:40–47
  82. Kibar Z, Vogan KJ, Groulx N, et al. Ltap, a mammalian homolog of Drosophila strabismus/van gogh, is altered in the mouse neural tube mutant loop-tail. Nat Genet. 2001;28:251–255
  83. Torban E, Patenaude AM, Leclerc S, et al. Genetic interaction between members of the Vangl family causes neural tube defects in mice. Proc Natl Acad Sci U S A. 2008;105:3449–3454
  84. Montcouquiol M, Rachel RA, Lanford PJ, et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature. 2003;423:173–177
  85. Lu X, Borchers AG, Jolicoeur C, et al. PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature. 2004;430:93–98
  86. Curtin JA, Quint E, Tsipouri V, et al. Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr Biol. 2003;13:1129–1133
  87. Hamblet NS, Lijam N, Ruiz-Lozano P, et al. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development. 2002;129:5827–5838
  88. Etheridge SL, Ray S, Li S, et al. Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development. PLoS Genet. 2008;4:e1000259
  89. Wang Y, Guo N, Nathans J. The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells. J Neurosci. 2006;26:2147–2156
  90. Le Caignec C, Boceno M, Saugier-Veber P, et al. Detection of genomic imbalances by array based comparative genomic hybridisation in fetuses with multiple malformations. J Med Genet. 2005;42:121–128
  91. Vissers LE, Veltman JA, van Kessel AG, et al. Identification of disease genes by whole genome CGH arrays. Hum Mol Genet. 2005;14:R215–R223
  92. Cook EH, Scherer SW. Coply-number variations associated with neuropsychiatric conditions. Nature. 2008;455:919–923
  93. Friedman JM, Baross A, Delaney AD, et al. Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation. Am J Hum Genet. 2006;79:500–513
  94. Zahir F, Friedman JM. The impact of array genomic hybridization on mental retardation research: A review of current technologies and their clinical utility. Clin Genet. 2007;72:271–287
  95. Schones DE, Zhao K. Genome-wide approaches to studying chromatin modifications. Nat Rev Genet. 2008;9:179–191
  96. Chang S, Wen S, Chen D, et al. Small regulatory RNAs in neurodevelopmental disorders. Hum Mol Genet. 2009;18:R18–R26
  97. Hosako H, Martin GS, Barrier M, et al. Gene and microRNA expression in p53-deficient day 8.5 mouse embryos. Birth Defects Res A Clin Mol Teratol. 2009;85:546–555
  98. Hodges E, Xuan Z, Balija V, et al. Genome-wide in situ exon capture for selective resequencing. Nat Genet. 2007;39:1522–1527

PII: S1071-9091(09)00041-2

doi: 10.1016/j.spen.2009.06.001

Seminars in Pediatric Neurology
Volume 16, Issue 3 , Pages 101-110 , September 2009