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Human Genetics

, Volume 115, Issue 6, pp 475–482 | Cite as

The human T locus and spina bifida risk

  • Liselotte E. Jensen
  • Sandrine Barbaux
  • Katy Hoess
  • Sven Fraterman
  • Alexander S. Whitehead
  • Laura E. MitchellEmail author
Original Investigation

Abstract

The transcription factor T is essential for mesoderm formation and axial development during embryogenesis. Embryonic genotype for a single-nucleotide polymorphism in intron 7 of T (TIVS7 T/C) has been associated with the risk of spina bifida in some but not all studies. We developed a novel genotyping assay for the TIVS7 polymorphism using heteroduplex generator methology. This assay was used to genotype spina bifida case—parent trios and the resulting data were analyzed using the transmission disequilibrium test and log-linear analyses. Analyses of these data demonstrated that heterozygous parents transmit the TIVS7-C allele to their offspring with spina bifida significantly more frequently than expected under the assumption of Mendelian inheritance (63 vs 50%, P=0.02). Moreover, these analyses suggest that the TIVS7-C allele acts in a dominant fashion, such that individuals carrying one or more copies of this allele have a 1.6-fold increased risk of spina bifida compared with individuals with zero copies. In silico analysis of the sequence surrounding this polymorphism revealed a potential target site for olfactory neuron-specific factor-1, a transcription factor expressed in the neural tube during development, spanning the polymorphic site. Several other putative, developmentally important and/or environmentally responsive transcription factor-binding sites were also identified close to the TIVS7 polymorphism. The TIVS7 polymorphism or a variant that is in linkage disequilibrium with the TIVS7 polymorphism may, therefore, play a role in T gene expression and influence the risk of spina bifida.

Keywords

Spina Bifida Transmission Disequilibrium Test Multivitamin Supplement Heterozygous Parent Informative Transmission 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This study was supported by grants from the National Institutes of Health (HD39195; HD39081), the Ethel Brown Foerderer Fund for Excellence and the General Clinical Research Center (M01-RR00240) of The Children’s Hospital of Philadelphia. The authors are grateful to their colleagues in The Spina Bifida Program (Dr. P. Pasquariello and J. Melchionni) and The Center for Fetal Diagnosis and Therapy (Dr. N.S. Adzick, Dr. M.P. Johnson, Dr. R.D. Wilson, L. Howell, S. Miesnik, M. Oxman and S. Kasperski) at The Children’s Hospital of Philadelphia, and in the Spinal Dysfunction Clinic at The A.I. duPont Hospital for Children (Dr. M. McManus and R. Gleeson), and to all of the families that have enrolled in this study.

References

  1. Andres V, Nadal-Ginard B, Mahdavi V (1992) Clox, a mammalian homeobox gene related to Drosophila cut, encodes DNA-binding regulatory proteins differentially expressed during development. Development 116:321–334PubMedGoogle Scholar
  2. Aufiero B, Neufeld EJ, Orkin SH (1994) Sequence-specific DNA binding of individual cut repeats of the human CCAAT displacement/cut homeodomain protein. Proc Natl Acad Sci USA 91:7757–7761PubMedGoogle Scholar
  3. Berry RJ, Li Z (2002) Folic acid alone prevents neural tube defects: evidence from the China study. Epidemiology 13:114–116CrossRefPubMedGoogle Scholar
  4. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, Mulinare J, Zhao P, Wong LC, Gindler J, Hong S, Correa A (1999) Prevention of neural-tube defects with folic acid in China. N Engl J Med 341:1485–1490CrossRefPubMedGoogle Scholar
  5. Bollage RJ, Siegfried Z, Cebra-Thomas JA, Garvey N, Davison EM, Silver LM (1994) An ancient family of embryonically expressed mouse genes sharing a conserved protein motif with the T locus. Nat Genet 7:383–389CrossRefPubMedGoogle Scholar
  6. Bowman RM, McLone DG, Grant JA, Tomita T, Ito JA (2001) Spina bifida outcome: a 25 year prospective. Pediatr Neurosurg 34:114–120CrossRefPubMedGoogle Scholar
  7. Brown KS, Cook M, Hoess K, Whitehead AS, Mitchell LE (2004) Evidence that the risk of spina bifida is influenced by genetic variation at the NOS3 locus. Birth Defects Res 70:101–106CrossRefGoogle Scholar
  8. Carpenter EM (2002) Hox genes and spinal cord development. Dev Neurosci 24:24–34CrossRefPubMedGoogle Scholar
  9. Clements D, Taylor HC, Herrmann BG, Stott D (1996) Distinct regulatory control of the Brachyury gene in axial and non-axial mesoderm suggests separation of mesoderm lineages early in mouse gastrulation. Mech Dev 56:139–149CrossRefPubMedGoogle Scholar
  10. Curtis D, Sham PC (1995) A note on the application of the transmission disequilibrium test when a parent is missing. Am J Hum Genet 56:811–821PubMedGoogle Scholar
  11. Czeizel AE, Dudas I (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 327:1832–1835PubMedGoogle Scholar
  12. Davis JA, Reed RR (1996) Role of Olf-1 and Pax-6 transcription factors in neurodevelopment. J Neurosci 16:5082–5094PubMedGoogle Scholar
  13. Denison MS, Nagy SR (2003) Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 43:309–334CrossRefPubMedGoogle Scholar
  14. Doolin MT, Barbaux S, McDonnell M, Hoess K, Whitehead AS, Mitchell LE (2002) Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida. Am J Hum Genet 71:1222–1226CrossRefPubMedGoogle Scholar
  15. Elwood JM, Little J, Elwood JH (1992) Epidemiology and control of neural tube defects. Oxford University Press, OxfordGoogle Scholar
  16. Finnell RH, Gould A, Spiegelstein O (2003) Pathobiology and genetic of neural tube defects. Epilepsia 44:14–23CrossRefGoogle Scholar
  17. Franceschi RT, Xiao G, Jiang D, Gopalakrishnan R, Yang S, Reith E (2003) Multiple signaling pathways converge on the Cbfa1/Runx2 transcription factor to regulate osteoblast differentiation. Connect Tissue Res 44:109–116Google Scholar
  18. Friso S, Choi SW (2002) Gene-nutrient interactions and DNA methylation. J Nutr 132:2382S–2387SPubMedGoogle Scholar
  19. Hill CS (2001) TGF-beta signalling pathways in early Xenopus development. Curr Opin Genet Dev 11:533–540CrossRefPubMedGoogle Scholar
  20. Hoffmann A, Czichos S, Kaps C, Bachner D, Mayer H, Kurkalli BG, Zilberman Y, Turgeman G, Pelled G, Gross G, Gazit D (2002) The T-box transcription factor Brachyury mediates cartilage development in mesenchymal stem cell line C3H10T1/2. J Cell Sci 115:769–781PubMedGoogle Scholar
  21. Jacob J, Briscoe J (2003) Gli proteins and the control of spinal-cord patterning. EMBO Rep 4:761–765CrossRefPubMedGoogle Scholar
  22. Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, Scott JM (1993) Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. QJM 86:703–708PubMedGoogle Scholar
  23. Kwan KM, Kirschner MW (2003) Xbra functions as a switch between cell migration and convergent extension in the Xenopus gastrula. Development 130:1961–1972CrossRefPubMedGoogle Scholar
  24. LaBonne C, Burke B, Whitman M (1995) Role of MAP kinase in mesoderm induction and axial patterning during Xenopus development. Development 121:1475–1486PubMedGoogle Scholar
  25. Latchman DS (1999) POU family transcription factors in the nervous system. J Cell Physiol 179:126–133CrossRefPubMedGoogle Scholar
  26. Lehmann OJ, Sowden JC, Carlsson P, Jordan T, Bhattacharya SS (2003) Fox’s in development and disease. Trends Genet 19:339–344CrossRefPubMedGoogle Scholar
  27. Lerchner W, Latinkic BV, Remacle JE, Huylebroeck D, Smith JC (2000) Region-specific activation of the Xenopus brachyury promoter involves active repression in ectoderm and endoderm: a study using transgenic frog embryos. Development 127:2729–2739PubMedGoogle Scholar
  28. Locklin RM, Riggs BL, Hicok KC, Horton HF, Byrne MC, Khosla S (2001) Assessment of gene regulation by bone morphogenetic protein 2 in human marrow stromal cells using gene array technology. J Bone Miner Res 16:2192–2204PubMedGoogle Scholar
  29. Lucock MD, Daskalakis I, Lumb CH, Schorah CJ, Levene MI (1998) Impaired regeneration of monoglutamyl tetrahydrofolate leads to cellular folate depletion in mothers affected by a spina bifida pregnancy. Mol Genet Metab 65:18–30CrossRefPubMedGoogle Scholar
  30. Martone R, Euskirchen G, Bertone P, Hartman S, Royce TE, Luscombe NM, Rinn JL, Nelson FK, Miller P, Gerstein M, Weissman S, Snyder M (2003) Distribution of NF-kappaB-binding sites across human chromosome 22. Proc Natl Acad Sci USA 100:12247–12252CrossRefPubMedGoogle Scholar
  31. Massague J, Blain SW, Lo RS (2000) TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103:295–309CrossRefPubMedGoogle Scholar
  32. Mills JL, McPartlin JM, Kirke PN, Lee YJ, Conley MR, Weir DG, Scott JM (1995) Homocysteine metabolism in pregnancies complicated by neural tube defects. Lancet 345:149–151CrossRefPubMedGoogle Scholar
  33. Mimura J, Fujii-Kuriyama Y (2003) Functional role of AhR in the expression of toxic effects by TCDD. Biochim Biophys Acta 1619:263–268CrossRefPubMedGoogle Scholar
  34. Mitchell LE (1997) Genetic epidemiology of birth defects: nonsyndromic cleft lip and neural tube defects. Epidemiol Rev 19:61–68PubMedGoogle Scholar
  35. Morrison K, Papapetrou C, Attwood J, Hol F, Lynch SA, Sampath A, Hamel B, Burn J, Sowden J, Stott D, Mariman E, Edwards YH (1996) Genetic mapping of the human homologue (T) of mouse T (Brachyury) and a search for allele association between human T and spina bifida. Hum Mol Genet 5:669–674CrossRefPubMedGoogle Scholar
  36. Morrison K, Papapetrou C, Hol FA, Mariman EC, Lynch SA, Bur NJ, Edwards YH (1998) Susceptibility to spina bifida; an association study of five candidate genes. Ann Hum Genet 62:379–396CrossRefPubMedGoogle Scholar
  37. MRC Vitamin Study Research Group (1991) Prevention of neural tube defects. Lancet 338:131–137CrossRefPubMedGoogle Scholar
  38. van den Oord EJCG, Vermunt JK (2000) Testing for linkage disequilibrium, maternal effects, and imprinting with (in)complete case-parent triads, by use of the computer program LEM. Am J Hum Genet 66:335–338CrossRefPubMedGoogle Scholar
  39. Richter B, Schultealbert AH, Koch MC (2002) Human T and risk for neural tube defects. J Med Genet 39:E14CrossRefPubMedGoogle Scholar
  40. Schacter B, Muir A, Gyves M, Tasin M (1979) HLA-A,B compatibility in parents of offspring with neural-tube defects or couples experiencing involuntary fetal wastage. Lancet 1:796–799CrossRefPubMedGoogle Scholar
  41. Schonemann MD, Ryan AK, Erkman L, McEvilly RJ, Bermingham J, Rosenfeld MG (1998) POU domain factors in neural development. Adv Exp Med Biol 449:39–53PubMedGoogle Scholar
  42. Shields DC, Ramsbottom D, Donoghue C, Pinjon E, Kirke PN, Molloy AM, Edwards YH, Mills JL, Mynett-Johnson L, Weir DG, Scott JM, Whitehead AS (2000) Association between historically high frequencies of neural tube defects and the human T homologue of mouse T (Brachyury). Am J Med Genet 92:206–211CrossRefPubMedGoogle Scholar
  43. Showell C, Binder O, Conlon FL (2004) T-box genes in early embryogenesis. Dev Dyn 229:201–218CrossRefPubMedGoogle Scholar
  44. Speer MC, Melvin EC, Viles KD, Bauer KA, Rampersaud E, Drake C, George TM, Enterline DS, Mackey JF, Worley G, Gilbert JR, Nye JS (2002) T locus shows no evidence for linkage disequilibrium or mutation in American Caucasian neural tube defect families. Am J Med Genet 110:215–218CrossRefPubMedGoogle Scholar
  45. Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506–516PubMedGoogle Scholar
  46. Steegers-Theunissen RPM, Boers GHJ, Trijbels FJM, Finkelstein JD, Blom HJ, Thomas CMG, Borm GF, Wouters MGAJ, Eskes TK (1994) Maternal hyperhomocysteinemia: a risk factor for neural tube defects? Metabolism 43:1475–1480CrossRefPubMedGoogle Scholar
  47. Sundaram N, Tao Q, Wylie C, Heasman J (2003) The role of maternal CREB in early embryogenesis of Xenopus laevis. Dev Biol 261:337–352CrossRefPubMedGoogle Scholar
  48. Thiagalingam A, De Bustros A, Borges M, Jasti R, Compton D, Diamond L, Mabry M, Ball DW, Baylin SB, Nelkin BD (1996) RREB-1, a novel zinc finger protein, is involved in the differentiation response to Ras in human medullary thyroid carcinomas. Mol Cell Biol 16:5335–5345PubMedGoogle Scholar
  49. Trembath D, Sherbondy AL, Vandyke DC, Shaw GM, Todoroff K, Lammer EJ, Finnell RH, Marker S, Lerner G, Murray JC (1999) Analysis of select folate pathway genes, PAX3, and human T in a Midwestern neural tube defect population. Teratology 59:331–341CrossRefPubMedGoogle Scholar
  50. Vermunt JK (1997) LEM: a general program for the analysis of categorical data. Tilberg University, TilbergGoogle Scholar
  51. Wacker SA, McNulty CL, Durston AJ (2004) The initiation of Hox gene expression in Xenopus laevis is controlled by Brachyury and BMP-4. Dev Biol 266:123–137CrossRefPubMedGoogle Scholar
  52. Walker AH, Najarian D, White DL, Jaffe JF, Kanetsky PA, Rebbeck TR (1999) Collection of genomic DNA by buccal swabs for polymerase chain reaction-based biomarker assays. Environ Health Perspect 107:517–520PubMedGoogle Scholar
  53. Wang SS, Tsai RY, Reed RR (1997) The characterization of the Olf-1/EBF-like HLH transcription factor family: implications in olfactory gene regulation and neuronal development. J Neurosci 17:4149–4158PubMedGoogle Scholar
  54. Weinberg CR (1999) Allowing for missing parents in genetic studies of case-parent triads. Am J Hum Genet 64:1186–1193CrossRefPubMedGoogle Scholar
  55. Weinberg CR, Wilcox AJ, Lie RT (1998) A log-linear approach to case-parent-triad data: assessing the effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am J Hum Genet 62:969–978CrossRefPubMedGoogle Scholar
  56. Wilcox AJ, Weinberg CR, Lie RT (1998) Distinguishing the effects of maternal and offspring genes through studies of “case-parent triads”. Am J Epidemiol 148:893–901PubMedGoogle Scholar
  57. Wong L-YC, Paulozzi LJ (2001) Survival of infants with spina bifida: a population based study, 1979–94. Paediatr Perinat Epidemiol 15:374–378CrossRefPubMedGoogle Scholar
  58. Yeo CY, Chen X, Whitman M (1999) The role of FAST-1 and Smads in transcriptional regulation by activin during early Xenopus embryogenesis. J Biol Chem 274:26584–26590CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Liselotte E. Jensen
    • 1
  • Sandrine Barbaux
    • 1
    • 4
  • Katy Hoess
    • 2
  • Sven Fraterman
    • 1
  • Alexander S. Whitehead
    • 1
  • Laura E. Mitchell
    • 3
    Email author
  1. 1.Department of Pharmacology and Center for PharmacogeneticsUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Center for Clinical Epidemiology and BiostatisticsUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Institute of Biosciences and TechnologyTexas A&M University System Health Science CenterHoustonUSA
  4. 4.INSERM U 525Faculté de Médecine Pitié-SalpétrièreParisFrance

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