Child's Nervous System

, Volume 35, Issue 6, pp 965–972 | Cite as

A functional indel polymorphism rs34396413 in TFAP2A intron-5 significantly increases female encephalocele risk in Han Chinese population

  • Ke Su
  • Shuxia Chen
  • Jianhong Ye
  • Lele Kuang
  • Ting Zhang
  • Hongyan Wang
  • Xueyan YangEmail author
Original Article



Transcription factor AP-2 alpha (TFAP2A) is an important transcriptional factor involved in various aspects of embryo development including neural tube closure. Tfap2a deficiency led to the failure of cranial neural-tube closure in mice and other model organisms. However, it remains largely unknown about the relationship between TFAP2A variants and human cranial neural tube defects (NTDs). The aim of this study was to find the association between TFAP2A intronic SNP rs3439413 and NTDs and to explore its function.


We found an indel polymorphism rs3439413 in TFAP2A intron-5 from our previous target sequencing project. In this study, we validate its association with human NTDs in Shanxi group containing 266 NTD cases and 295 matched controls. Then, we investigated its function on transcriptional activity by dual-luciferase assays and EMSA.


The minor allele of rs34396413 significantly increased the risk of NTD in a Han Chinese population of Shanxi Province (P = 0.0082, OR = 1.45, 95%CI = 1.10–1.90), especially the risk of encephalocele for female (P = 0.0064, OR = 2.46, 95%CI = 1.22–4.94). Functional analysis revealed the minor allele of rs34396413 decreases transcriptional activity and attenuates transcription factor binding affinity.


We have demonstrated that the minor allele of rs34396413 was a risk factor of NTD in the Shanxi group, providing new insight into the study of NTD etiology.


Neural tube defects TFAP2A Intronic variant rs34396413 Enhancer 



We sincerely thank all the patients and control individuals for their participation in this study.

Funding information

This work is supported by grants from the National Key Basic Research Program of China (2016YFC1000502 to X. Yang and H. Wang), the National Natural Science Foundation of China (81472050 to X. Yang and 81430005, 31521003, 81741048 to H. Wang), and Open project of National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices (2016KF04 to X Yang).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were approved by the Ethics Committee of the School of Life Sciences, Fudan University.

Research involving human participants and animals

This article did not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in this study.

Supplementary material

381_2019_4131_MOESM1_ESM.pdf (199 kb)
ESM 1 (PDF 198 kb)


  1. 1.
    Aliferis K, Stoetzel C, Pelletier V, Helle S, Angioi-Duprez K, Vigneron J, Leheup B, Marion V, Dollfus H (2011) A novel TFAP2A mutation in familial branchio-oculo-facial syndrome with predominant ocular phenotype. Ophthalmic Genet 32:250–255CrossRefPubMedGoogle Scholar
  2. 2.
    Barrallo-Gimeno A, Holzschuh J, Driever W, Knapik EW (2004) Neural crest survival and differentiation in zebrafish depends on mont blanc/tfap2a gene function. DEVELOPMENT 131:1463–1477CrossRefPubMedGoogle Scholar
  3. 3.
    Copp AJ, Greene ND (2010) Genetics and development of neural tube defects. J Pathol 220:217–230PubMedPubMedCentralGoogle Scholar
  4. 4.
    Feng W, Huang J, Zhang J, Williams T (2008) Identification and analysis of a conserved Tcfap2a intronic enhancer element required for expression in facial and limb bud mesenchyme. Mol Cell Biol 28:315–325CrossRefPubMedGoogle Scholar
  5. 5.
    Gunes N, Cengiz FB, Duman D, Dervisoglu S, Tekin M, Tuysuz B (2014) Branchio-oculo-facial syndrome in a newborn caused by a novel TFAP2A mutation. GENET COUNSEL 25:41–47PubMedGoogle Scholar
  6. 6.
    Hook EB (2000) Neural-tube defects. N Engl J Med 342:1136–1137PubMedGoogle Scholar
  7. 7.
    Kibar Z, Capra V, Gros P (2007) Toward understanding the genetic basis of neural tube defects. Clin Genet 71:295–310CrossRefPubMedGoogle Scholar
  8. 8.
    Klootwijk R, Hol FA, Wu M, Willemen JJ, Groenen P, Hamel B, Straatman H, Steegers-Theunissen RP, Mariman EC, Franke B (2003) Genetic variation analysis of MLP, TFAP2A, and CSK in patients with neural tube defects. J Med Genet 40:e43–e443Google Scholar
  9. 9.
    Knight RD, Nair S, Nelson SS, Afshar A, Javidan Y, Geisler R, Rauch GJ, Schilling TF (2003) Lockjaw encodes a zebrafish tfap2a required for early neural crest development. DEVELOPMENT 130:5755–5768CrossRefPubMedGoogle Scholar
  10. 10.
    Li Z, Ren A, Zhang L, Ye R, Li S, Zheng J, Hong S, Wang T, Li Z (2006) Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China. Birth Defects Res A Clin Mol Teratol 76:237–240CrossRefGoogle Scholar
  11. 11.
    Lu W, Guzman AR, Yang W, Chapa CJ, Shaw GM, Greene RM, Pisano MM, Lammer EJ, Finnell RH, Zhu H (2010) Genes encoding critical transcriptional activators for murine neural tube development and human spina bifida: a case-control study. BMC Med Genet 11:141CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker HJ, Zori RT, Burch MN, Clemens M, Mulliken JB, Smith R, Lin AE (2008) TFAP2A mutations result in branchio-oculo-facial syndrome. Am J Hum Genet 82:1171–1177CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Nottoli T, Hagopian-Donaldson S, Zhang J, Perkins A, Williams T (1998) AP-2-null cells disrupt morphogenesis of the eye, face, and limbs in chimeric mice. Proc Natl Acad Sci U S A 95:13714–13719CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Qiao X, Liu Y, Li P, Chen Z, Li H, Yang X, Finnell RH, Yang Z, Zhang T, Qiao B, Zheng Y, Wang H (2016) Genetic analysis of rare coding mutations in CELSR1-3 in Chinese congenital heart and neural tube defects. Clin Sci (Lond)Google Scholar
  15. 15.
    Sato T, Samura O, Kato N, Taniguchi K, Takahashi K, Ito Y, Aoki H, Kobayashi M, Migita O, Okamoto A, Hata K (2018) Novel TFAP2A mutation in a Japanese family with branchio-oculo-facial syndrome. Hum Genome Var 5:5CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Schorle H, Meier P, Buchert M, Jaenisch R, Mitchell PJ (1996) Transcription factor AP-2 essential for cranial closure and craniofacial development. NATURE 381:235–238CrossRefPubMedGoogle Scholar
  17. 17.
    Stegmann K, Boecker J, Richter B, Capra V, Finnell RH, Ngo E, Strehl E, Ermert A, Koch MC (2001) A screen for mutations in human homologues of mice exencephaly genes Tfap2 alpha and Msx2 in patients with neural tube defects. TERATOLOGY 63:167–175CrossRefPubMedGoogle Scholar
  18. 18.
    Wallingford JB, Niswander LA, Shaw GM, Finnell RH (2013) The continuing challenge of understanding, preventing, and treating neural tube defects. SCIENCE 339:1222002CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Xu X, Liu Z, Huang H, Zheng K, Hu X, Zhang Z, Qiu M (2017) AP-2alpha and AP-2beta regulate dorsal interneuron specification in the spinal cord. NEUROSCIENCE 340:232–242CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang J, Hagopian-Donaldson S, Serbedzija G, Elsemore J, Plehn-Dujowich D, McMahon AP, Flavell RA, Williams T (1996) Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. NATURE 381:238–241CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang J, Williams T (2003) Identification and regulation of tissue-specific cis-acting elements associated with the human AP-2alpha gene. Dev Dyn 228:194–207CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life SciencesFudan UniversityShanghaiChina
  2. 2.Beijing Municipal Key Laboratory of Child Development and NutriomicsCapital Institute of PediatricsBeijingChina
  3. 3.Institute of Reproduction and DevelopmentObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
  4. 4.Key Laboratory of Reproduction Regulation of NPFPCObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina

Personalised recommendations