Neurological Sciences

, Volume 35, Issue 11, pp 1701–1706

Polymorphisms in FZD3 and FZD6 genes and risk of neural tube defects in a northern Han Chinese population

  • Ou-Yan Shi
  • Hui-Yun Yang
  • Yong-Ming Shen
  • Wei Sun
  • Chun-You Cai
  • Chun-Quan Cai
Original Article


Neural tube defects (NTDs) are the most common and severe malformations of the central nervous system. The association of single nucleotide polymorphisms (SNPs) of the Frizzled 3 (FZD3) and Frizzled 6 (FZD6) genes and NTDs in the Han population of northern China was principally studied. One synonymous SNP (rs2241802) in FZD3 gene and three nonsynonymous SNPs (rs827528, rs3808553 and rs12549394) in FZD6 gene were analyzed by polymerase chain reaction (PCR) and sequencing methods in 135 NTD patients and 135 normal controls. The allele, genotype and haplotype frequencies were calculated and analyzed to examine the relationship between FZD3/FZD6 SNPs and NTDs. Both T allele and TT genotype frequencies of the FZD6 rs3808553 loci in the NTDs group were significantly higher than those in the controls, and children with T allele and TT genotype were associated with increased NTDs risk (OR = 1.575, 95 % CI 1.112–2.230, P = 0.010 and OR = 2.811, 95 % CI 1.325–5.967, P = 0.023, respectively). There were no differences among different genotypes or alleles in other three SNPs. Haplotypes A-G-C and A-T-C in FZD6 were found associated with NTDs in the case–control study (OR = 0.560, 95 % CI 0.378–0.830, P = 0.004 and OR = 1.670, 95 % CI 1.126–2.475, P = 0.011, respectively). The rs3808553 of FZD6 is obviously associated with NTDs in Han population of northern China. The TT genotype may increase risk for NTDs.


Neural tube defects FZD3 FZD6 Gene polymorphisms 

Supplementary material

10072_2014_1815_MOESM1_ESM.jpg (1 mb)
Supplementary material 1 (JPEG 1038 kb)


  1. 1.
    Cai C, Zhang Q, Yang W, Shen C (2008) Giant congenital melanocytic nevus coexistent with Chiari II malformation. Neuropediatrics 39(5):272–275PubMedCrossRefGoogle Scholar
  2. 2.
    Rossi A, Cama A, Piatelli G, Ravegnani M, Biancheri R, Tortori-Donati P (2004) Spinal dysraphism: MR imaging rationale. J Neuroradiol 31(1):3–24PubMedCrossRefGoogle Scholar
  3. 3.
    Beaudin AE, Stover PJ (2009) Insights into metabolic mechanisms underlying folate-responsive neural tube defects: a minireview. Birth Defects Res A Clin Mol Teratol 85(4):274–284PubMedCrossRefGoogle Scholar
  4. 4.
    De Marco P, Merello E, Calevo MG, Mascelli S, Raso A, Cama A, Capra V (2006) Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G. A polymorphism for neural tube defect risk. J Hum Genet 51(2):98–103PubMedCrossRefGoogle Scholar
  5. 5.
    De Marco P, Calevo MG, Moroni A, Merello E, Raso A, Finnell RH, Zhu H, Andreussi L, Cama A, Capra V (2003) Reduced folate carrier polymorphism (80A/G) and neural tube defects. Eur J Hum Genet 11(3):245–252PubMedCrossRefGoogle Scholar
  6. 6.
    Kibar Z, Capra V, Gros P (2007) Toward understanding the genetic basis of neural tube defects. Clin Genet 71(4):295–310PubMedCrossRefGoogle Scholar
  7. 7.
    O’leary VB, Pangilinan F, Cox C, Parle-McDermott A, Conley M, Molloy AM, Kirke PN, Mills JL, Brody LC, Scott JM, Members of the Birth Defects Research Group (2006) Reduced folate carrier polymorphisms and neural tube defect risk. Mol Genet Metab 87(4):364–369PubMedCrossRefGoogle Scholar
  8. 8.
    Van der Linden IJ, Afman LA, Heil SG, Blom HJ (2006) Genetic variation in genes of folate metabolism and neural-tube defect risk. Proc Nutr Soc 65(2):204–215PubMedCrossRefGoogle Scholar
  9. 9.
    De Marco P, Merello E, Capra V (2011) Neural tube defects: genetic causes and prevention. Biofactor 37(4):261–268CrossRefGoogle Scholar
  10. 10.
    Bartsch O, Kirmes I, Thiede A, Lechno S, Gocan H, Florian IS, Haaf T, Zechner U, Sabova L, Horn F (2012) Novel VANGL1 gene mutations in 144 Slovakian, Romanian and German patients with neural tube defects. Mol Syndromol 3(2):76–81PubMedCentralPubMedGoogle Scholar
  11. 11.
    Kibar Z, Bosoi CM, Kooistra M, Salem S, Finnell RH, De Marco P, Merello E, Bassuk AG, Capra V, Gros P (2009) Novel mutations in VANGL1 in neural tube defects. Hum Mutat 30(7):E706–E715PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Kibar Z, Torban E, McDearmid JR, Reynolds A, Berghout J, Mathieu M, Kirillova I, De Marco P, Merello E, Hayes JM, Wallingford JB, Drapeau P, Capra V, Gros P (2007) Mutations in VANGL1 associated with neural-tube defects. N Engl J Med 356(14):1432–1437PubMedCrossRefGoogle Scholar
  13. 13.
    Kibar Z, Salem S, Bosoi CM, Pauwels E, De Marco P, Merello E, Bassuk AG, Capra V, Gros P (2011) Contribution of VANGL2 mutations to isolated neural tube defects. Clin Genet 80(1):76–82PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Lei YP, Zhang T, Li H, Wu BL, Jin L, Wang HY (2010) VANGL2 mutations in human cranial neural-tube defects. N Engl J Med 362(23):2232–2235PubMedCrossRefGoogle Scholar
  15. 15.
    Allache R, De Marco P, Merello E, Capra V, Kibar Z (2012) Role of the planar cell polarity gene CELSR1 in neural tube defects and caudal agenesis. Birth Defects Res A Clin Mol Teratol 94(3):176–181PubMedCrossRefGoogle Scholar
  16. 16.
    Robinson A, Escuin S, Doudney K, Vekemans M, Stevenson RE, Greene ND, Copp AJ, Stanier P (2012) Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis. Hum Mutat 33(2):440–447PubMedCrossRefGoogle Scholar
  17. 17.
    Simons M, Mlodzik M (2008) Planar cell polarity signaling: from fly development to human disease. Annu Rev Genet 42:517–540PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Wang Y, Guo N, Nathans J (2006) The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells. J Neurosci 26(8):2147–2156PubMedCrossRefGoogle Scholar
  19. 19.
    De Marco P, Merello E, Rossi A, Piatelli G, Cama A, Kibar Z, Capra V (2012) FZD6 is a novel gene for human neural tube defects. Hum Mutat 33(2):384–390PubMedCrossRefGoogle Scholar
  20. 20.
    Schulte G, Bryja V (2007) The Frizzled family of unconventional G-protein-coupled receptors. Trends Pharmacol Sci 28(10):518–525PubMedCrossRefGoogle Scholar
  21. 21.
    Robitaille J, MacDonald ML, Kaykas A, Sheldahl LC, Zeisler J, Dubé MP, Zhang LH, Singaraja RR, Guernsey DL, Zheng B, Siebert LF, Hoskin-Mott A, Trese MT, Pimstone SN, Shastry BS, Moon RT, Hayden MR, Goldberg YP, Samuels ME (2002) Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet 32(2):326–330PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2014

Authors and Affiliations

  • Ou-Yan Shi
    • 1
  • Hui-Yun Yang
    • 2
  • Yong-Ming Shen
    • 3
  • Wei Sun
    • 1
  • Chun-You Cai
    • 4
  • Chun-Quan Cai
    • 5
  1. 1.School of Basic Medical SciencesTianjin Medical UniversityTianjinChina
  2. 2.School of Biomedical EngineeringTianjin Medical UniversityTianjinChina
  3. 3.Department of Clinical LaboratoryTianjin Children’s HospitalTianjinChina
  4. 4.Research Center of Basic Medical SciencesTianjin Medical UniversityTianjinChina
  5. 5.Department of NeurosurgeryTianjin Children’s HospitalTianjinChina

Personalised recommendations