2ej4

Structural highlights

Disease

[ZIC3_HUMAN] Defects in ZIC3 are the cause of visceral heterotaxy X-linked type 1 (HTX1) [MIM:306955]. A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. It results in an abnormal arrangement of visceral organs, and a wide variety of congenital defects. Clinical features of visceral heterotaxy X-linked type 1 include dextrocardia, corrected transposition of great arteries, ventricular septal defect, patent ductus arteriosus, pulmonic stenosis, situs inversus viscerum, and asplenia and/or polysplenia.^{[1] [2] [3] [4] [5]} Defects in ZIC3 are a cause of VACTERL association X-linked with or without hydrocephalus (VACTERLX) [MIM:314390]. A syndrome characterized by vertebral anomalies, anal atresia, cardiac malformations, tracheoesophageal fistula, renal anomalies (urethral atresia with hydronephrosis), and limb anomalies (hexadactyly, humeral hypoplasia, radial aplasia, and proximally placed thumb). Some patients may have hydrocephalus. Some cases of VACTERL-H are associated with increased chromosome breakage and rearrangement.^[6] Defects in ZIC3 are the cause of congenital heart defects, multiple types, 1, X-linked (CHTD1) [MIM:306955]. A disorder characterized by congenital developmental abnormalities involving structures of the heart. Common defects include transposition of the great arteries, aortic stenosis, atrial septal defect, ventricular septal defect, pulmonic stenosis, and patent ductus arteriosus. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. Some patients with CHTD1 also have cardiac arrhythmias, which may be due to the anatomic defect itself or to surgical interventions.^{[7] [8]}

Function

[ZIC3_HUMAN] Acts as transcriptional activator. Required in the earliest stages in both axial midline development and left-right (LR) asymmetry specification. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'.^[9]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Zhu L, Zhou G, Poole S, Belmont JW. Characterization of the interactions of human ZIC3 mutants with GLI3. Hum Mutat. 2008 Jan;29(1):99-105. PMID:17764085 doi:10.1002/humu.20606
2. ↑ Hatayama M, Tomizawa T, Sakai-Kato K, Bouvagnet P, Kose S, Imamoto N, Yokoyama S, Utsunomiya-Tate N, Mikoshiba K, Kigawa T, Aruga J. Functional and structural basis of the nuclear localization signal in the ZIC3 zinc finger domain. Hum Mol Genet. 2008 Nov 15;17(22):3459-73. Epub 2008 Aug 20. PMID:18716025 doi:ddn239
3. ↑ Gebbia M, Ferrero GB, Pilia G, Bassi MT, Aylsworth A, Penman-Splitt M, Bird LM, Bamforth JS, Burn J, Schlessinger D, Nelson DL, Casey B. X-linked situs abnormalities result from mutations in ZIC3. Nat Genet. 1997 Nov;17(3):305-8. PMID:9354794 doi:10.1038/ng1197-305
4. ↑ Ware SM, Peng J, Zhu L, Fernbach S, Colicos S, Casey B, Towbin J, Belmont JW. Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am J Hum Genet. 2004 Jan;74(1):93-105. Epub 2003 Dec 16. PMID:14681828 doi:S0002-9297(07)61948-X
5. ↑ Chhin B, Hatayama M, Bozon D, Ogawa M, Schon P, Tohmonda T, Sassolas F, Aruga J, Valard AG, Chen SC, Bouvagnet P. Elucidation of penetrance variability of a ZIC3 mutation in a family with complex heart defects and functional analysis of ZIC3 mutations in the first zinc finger domain. Hum Mutat. 2007 Jun;28(6):563-70. PMID:17295247 doi:10.1002/humu.20480
6. ↑ Wessels MW, Kuchinka B, Heydanus R, Smit BJ, Dooijes D, de Krijger RR, Lequin MH, de Jong EM, Husen M, Willems PJ, Casey B. Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder? J Med Genet. 2010 May;47(5):351-5. doi: 10.1136/jmg.2008.060913. PMID:20452998 doi:10.1136/jmg.2008.060913
7. ↑ Zhu L, Zhou G, Poole S, Belmont JW. Characterization of the interactions of human ZIC3 mutants with GLI3. Hum Mutat. 2008 Jan;29(1):99-105. PMID:17764085 doi:10.1002/humu.20606
8. ↑ Ware SM, Peng J, Zhu L, Fernbach S, Colicos S, Casey B, Towbin J, Belmont JW. Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am J Hum Genet. 2004 Jan;74(1):93-105. Epub 2003 Dec 16. PMID:14681828 doi:S0002-9297(07)61948-X
9. ↑ Zhu L, Zhou G, Poole S, Belmont JW. Characterization of the interactions of human ZIC3 mutants with GLI3. Hum Mutat. 2008 Jan;29(1):99-105. PMID:17764085 doi:10.1002/humu.20606