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Gene Review

ZIC3  -  Zic family member 3

Homo sapiens

Synonyms: HTX, HTX1, VACTERLX, ZNF203, Zinc finger protein 203, ...
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Disease relevance of ZIC3

  • These patients occasionally also show spina bifida, indicating that genetic variation in human ZIC3 may contribute to other congenital malformations, including neural tube defects [1].
  • The frameshift allele is also associated with situs inversus among some heterozygous females, suggesting that ZIC3 functions in the earliest stages of LR-axis formation [2].
  • Mutations in the zinc finger transcription factor ZIC3 cause X-linked heterotaxy and have also been identified in patients with isolated congenital heart disease (CHD) [3].
  • Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects [3].
  • METHODS: Neovascularization was investigated in 14 explanted hearts from patients with ischemic cardiomyopathy (ICMP) who had been bridged to HTX with PGE-1 (8+/-1 mg/kg/min, 97+/-75.6 days) and compared with 14 hearts who did not receive PGE-1 prior to HTX [4].

High impact information on ZIC3

  • From this chromosomal region we have positionally cloned ZIC3, a gene encoding a putative zinc-finger transcription factor [2].
  • X-linked situs abnormalities result from mutations in ZIC3 [2].
  • Functional analysis of all currently known ZIC3 point mutations indicates that mutations in the putative zinc finger DNA binding domain and in the N-terminal domain result in loss of reporter gene transactivation [3].
  • It is surprising that transfection studies demonstrate aberrant cytoplasmic localization resulting from mutations between amino acids 253-323 of the ZIC3 protein, indicating that the pathogenesis of a subset of ZIC3 mutations results at least in part from failure of appropriate nuclear localization [3].
  • 1. Further analysis of this family has revealed two recombinations that place HTX1 between DXS300 and DXS1062, an interval spanning approximately 1.3 Mb in Xq26 [5].

Chemical compound and disease context of ZIC3


Biological context of ZIC3


Anatomical context of ZIC3

  • Disruption of gradient expression of Zic3 by retroviral overexpression resulted in mis-targeting of retinal axons and some axons misrouted to the sub-retinal space at the photoreceptor side of the retina [10].
  • A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice [11].
  • Zic3 is not expressed in the node during primitive streak stages but is expressed in and around the node beginning from the head fold stages of development [12].
  • The Zic3 expression in the mesoderm is induced by activin (beta) or Vg1, which are also involved in the left-sided signal in L-R specification [13].
  • Direct titration of quinacrine into suspensions of a high concentration of AcChR-associated membranes yielded an upper limit to the binding stoichiometry of 1.4 HTX- or PCP-displaceable quinacrine binding sites/AcChR functional units [14].

Associations of ZIC3 with chemical compounds

  • Specific labeling required the presence of high concentration of agonist and was inhibited by reversible noncompetitive antagonists including proadifen, meproadifen, perhydrohistrionicotoxin (HTX), and tetracaine when present at concentrations consistent with the binding affinity of these compounds for the allosteric antagonist site [15].
  • Especially within the 1st year after HTX, luminal loss is influenced not only by an increase in plaque area but by a decrease in total vessel volume as well [16].
  • Acetylcholine induced significant epicardial vasodilation in control subjects and vasoconstriction in HTX, as well as a marked increase in CBF in both groups [17].
  • METHODS: Genotyping and assessment of fasting HCY levels were performed in a cohort of 146 HTX recipients and correlated to the onset and progression of CAVD, assessed by serial angiography [18].
  • In HTX, phenylephrine infusion increased Ees, Ea, EW, PVA, and MVO2 without modifying Ees/Ea, EW/PVA, PVA/MVO2, and EW/MVO2 [19].

Other interactions of ZIC3


Analytical, diagnostic and therapeutic context of ZIC3

  • Pattern of remodeling was analyzed in patients "early" (n = 15, BL study 1.4+/-0.7 months after heart transplantation [HTX]) compared with "late" after HTX (n = 15, BL 46.1+/-29.1 months) [16].
  • Measurements were made at baseline in 11 control subjects and 9 heart transplant recipients (HTX) without rejection and were repeated after phenylephrine in the latter group [19].
  • BACKGROUND: The aim of the present analysis was to define the role of simultaneous heart and kidney transplantation (HNTX) using organs from the same donor by evaluation of clinical strategy and achieved outcome compared with a reference group of concurrently single heart transplant (HTX) and kidney transplant (NTX) recipients [23].
  • Only 3 patients (4%) in the control group had PRA > 10% at the time of HTX [24].
  • CONCLUSION: Patients with LVAD support before HTX do not appear to be at increased risk for significant allograft rejection in the first year or for death within the first 2 years after transplantation [24].


  1. A deletion encompassing Zic3 in bent tail, a mouse model for X-linked neural tube defects. Klootwijk, R., Franke, B., van der Zee, C.E., de Boer, R.T., Wilms, W., Hol, F.A., Mariman, E.C. Hum. Mol. Genet. (2000) [Pubmed]
  2. X-linked situs abnormalities result from mutations in ZIC3. Gebbia, M., Ferrero, G.B., Pilia, G., Bassi, M.T., Aylsworth, A., Penman-Splitt, M., Bird, L.M., Bamforth, J.S., Burn, J., Schlessinger, D., Nelson, D.L., Casey, B. Nat. Genet. (1997) [Pubmed]
  3. Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Ware, S.M., Peng, J., Zhu, L., Fernbach, S., Colicos, S., Casey, B., Towbin, J., Belmont, J.W. Am. J. Hum. Genet. (2004) [Pubmed]
  4. Clinical and experimental evidence of prostaglandin E1-induced angiogenesis in the myocardium of patients with ischemic heart disease. Mehrabi, M.R., Serbecic, N., Tamaddon, F., Kaun, C., Huber, K., Pacher, R., Wild, T., Mall, G., Wojta, J., Glogar, H.D. Cardiovasc. Res. (2002) [Pubmed]
  5. A submicroscopic deletion in Xq26 associated with familial situs ambiguus. Ferrero, G.B., Gebbia, M., Pilia, G., Witte, D., Peier, A., Hopkin, R.J., Craigen, W.J., Shaffer, L.G., Schlessinger, D., Ballabio, A., Casey, B. Am. J. Hum. Genet. (1997) [Pubmed]
  6. Multi-chemothermoimmunotherapy for human colon adenocarcinoma in vitro. Klostergaard, J., Leroux, M.E., Hsu, H.A., Hsi, B.P., Siddik, Z.H., Danhauser, L.L., Tomasovi, S.P. Cancer Chemother. Pharmacol. (1996) [Pubmed]
  7. Myocardial contrast echocardiography for assessment of papaverine vasodilator response in patients with angiographically normal coronary arteries and in patients after orthotopic heart transplantation. Klauss, V., Mudra, H., Sbarouni, E., Meissner, O., Metz, J., Theisen, K. Zeitschrift für Kardiologie. (1995) [Pubmed]
  8. Situs ambiguus in a female fetus with balanced (X;21) translocation--evidence for functional nullisomy of the ZIC3 gene? Fritz, B., Kunz, J., Knudsen, G.P., Louwen, F., Kennerknecht, I., Eiben, B., Orstavik, K.H., Friedrich, U., Rehder, H. Eur. J. Hum. Genet. (2005) [Pubmed]
  9. Nuclear import and export signals are essential for proper cellular trafficking and function of ZIC3. Bedard, J.E., Purnell, J.D., Ware, S.M. Hum. Mol. Genet. (2007) [Pubmed]
  10. Disruption of gradient expression of Zic3 resulted in abnormal intra-retinal axon projection. Zhang, J., Jin, Z., Bao, Z.Z. Development (2004) [Pubmed]
  11. A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Purandare, S.M., Ware, S.M., Kwan, K.M., Gebbia, M., Bassi, M.T., Deng, J.M., Vogel, H., Behringer, R.R., Belmont, J.W., Casey, B. Development (2002) [Pubmed]
  12. Overlapping and distinct expression domains of Zic2 and Zic3 during mouse gastrulation. Elms, P., Scurry, A., Davies, J., Willoughby, C., Hacker, T., Bogani, D., Arkell, R. Gene Expr. Patterns (2004) [Pubmed]
  13. Zic3 is involved in the left-right specification of the Xenopus embryo. Kitaguchi, T., Nagai, T., Nakata, K., Aruga, J., Mikoshiba, K. Development (2000) [Pubmed]
  14. Transverse localization of the quinacrine binding site on the Torpedo acetylcholine receptor. Arias, H.R., Valenzuela, C.F., Johnson, D.A. J. Biol. Chem. (1993) [Pubmed]
  15. Reaction of [3H]meproadifen mustard with membrane-bound Torpedo acetylcholine receptor. Dreyer, E.B., Hasan, F., Cohen, S.G., Cohen, J.B. J. Biol. Chem. (1986) [Pubmed]
  16. Volumetric remodeling of the proximal left coronary artery: early versus late after heart transplantation. Pethig, K., Heublein, B., Meliss, R.R., Haverich, A. J. Am. Coll. Cardiol. (1999) [Pubmed]
  17. Effects of bradykinin on coronary blood flow and vasomotion in transplant patients. Aptecar, E., Teiger, E., Dupouy, P., Benvenuti, C., Kern, M.J., Woscoboinik, J., Sediame, S., Pernes, J.M., Castaigne, A., Loisance, D., Dubois-Randé, J.L. J. Am. Coll. Cardiol. (2000) [Pubmed]
  18. Cardiac allograft vascular disease after orthotopic heart transplantation: methylenetetrahydrofolate reductase gene polymorphism C677T does not account for rapidly progressive forms. Pethig, K., Hoffmann, A., Heublein, B., Timke, A., Gross, G., Haverich, A. Transplantation (2000) [Pubmed]
  19. Ventriculoarterial coupling and left ventricular efficiency in heart transplant recipients. Arnoult, F., Loiseau, A., Aptecar, E., Loisance, D., Nitenberg, A. Transplantation (1997) [Pubmed]
  20. Genetic variants in ZIC1, ZIC2, and ZIC3 are not major risk factors for neural tube defects in humans. Klootwijk, R., Groenen, P., Schijvenaars, M., Hol, F., Hamel, B., Straatman, H., Steegers-Theunissen, R., Mariman, E., Franke, B. Am. J. Med. Genet. A (2004) [Pubmed]
  21. Molecular genetics of heterotaxy syndromes. Belmont, J.W., Mohapatra, B., Towbin, J.A., Ware, S.M. Curr. Opin. Cardiol. (2004) [Pubmed]
  22. Identification of a phylogenetically conserved activin-responsive enhancer in the Zic3 gene. Weber, J.R., Sokol, S.Y. Mech. Dev. (2003) [Pubmed]
  23. Simultaneous heart and kidney transplantation as treatment for end-stage heart and kidney failure. Laufer, G., Kocher, A., Grabenwöger, M., Berlakovich, G.A., Zuckermann, A., Ofner, P., Grimm, M., Steininger, R., Mühlbacher, F. Transplantation (1997) [Pubmed]
  24. Development of anti-major histocompatibility complex class I or II antibodies following left ventricular assist device implantation: effects on subsequent allograft rejection and survival. Pagani, F.D., Dyke, D.B., Wright, S., Cody, R., Aaronson, K.D. J. Heart Lung Transplant. (2001) [Pubmed]
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