Overview
X-linked heterotaxy (HTX-1, MIM 306955) is a rare developmental disorder characterized by disturbances in embryonic laterality and other midline developmental field defects. We are using this genetic defect as an inroad to study the mechanistic underpinnings of early axis formation and its importance for subsequent cardiogenesis.
HTX1 results from mutations in ZIC3, a member of the GLI transcription factor superfamily. Individuals with HTX1 have a number of congenital malformations including complex congenital heart disease, gut malrotation, abnormalities of spleen position and number, and renal and anal malformations. The phenotype is widely variable. We are interested in understanding the role of Zic3 in body pattern formation and the development of left-right asymmetry. We have developed a mouse model of X-linked heterotaxy by targeted deletion of the murine Zic3 locus and are using this and other mouse models to investigate the functions of Zic3. We are specifically focusing on its interactions with other molecular components of the left-right patterning pathway immediately prior to and during cardiac looping. A second focus, utilizing both mouse mouse models and Xenopus, is on the role of Zic3 during gastrulation.
In collaboration with the Cardiovascular Genetics Clinic at Baylor College of Medicine, we have performed ZIC3 mutation screening on individuals with familial and sporadic heterotaxy in order to more clearly define the clinical spectrum of this disorder. Further details are available at www.cardiogene.org. This molecular data is being utilized to engineer similar mutations in the mouse in order to create mouse models of human malformation. Both in vitro and in vivo studies are ongoing to delineate genotype-phenotype correlations and further explore the functional domains of the ZIC3 gene.
Related Publications
Purandare, S. *, Ware, S.M. *, Kwan KM, Gebbia, M, Bassi MT, Deng JM, Vogel, H, Behringer RR, Belmont JW, Casey B. A complex syndrome of left right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Development 129: 2293-2302, 2002
Ware SM and Belmont JW. ZIC3, CFC1, ACVR2B and EBAF and the Visceral Heterotaxies. In Epstein C, Erickson RP and Wynshaw-Boris A eds, Molecular Basis of Inborn Errors of Development (Oxford University Press), 2004.
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. American Journal of Human Genetics 74: 93-105, 2004.
Elefteriou F, Takeda S, Ebihara, K, Magre J,Patano N, Ae Kim C, Ogawa Y, Liu X, Ware SM, Craigen WJ, Robert JJ, Vinson, C, Nakao K, Capeau J, Karsenty G. Serum leptin level is a regulator of bone mass. Proceedings of the National Academy of Sciences of the United States of America 101: 3258-3263, 2004.
Belmont JW, Mohapatra B, Towbin JA, Ware, SM. Molecular genetics of heterotaxy syndromes. Current Opinion in Cardiology 19(3): 216-20, 2004.
Scaglia F, Towbin JA, Craigen WJ, Belmont JW, Smith EO, Neish SR, Ware SM, Bowles KR, Hunter J, Fernbach SD, Vladutiu G, Wong L-JC, Vogel H. Clinical Spectrum, Morbidity, and Mortality in 113 Pediatric Patients with Mitochondrial Disease. Pediatrics 114: 925-931, 2004.
Jeffries JL, Belmont JW, Craigen WJ, Ware SM, Fernbach SD, Neish SR, O'Brien Smith E, Towbin JA. Genetic Predictors and Reverse Remodeling of Dilated Cardiomyopathy in Muscular Dystrophy. Circulation 112: 2799-2804, 2005.
Zhu, L, Belmont JW, Ware SM. Genetics of Human Heterotaxias. European Journal of Human Genetics 14: 17-25, 2006.
Chen, C*, Ware, SM*, Sato A, Houston-Hawkins, DE, Habas, R, Matzuk, MM, Shen, MM, Brown, CW. The Vg1-related protein GDF3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo. Development 133: 319-329, 2006. *co-first authors.
Ware, SM, Harutyunyan, KG, Belmont, JW. Zic3 is critical for early embryonic patterning during gastrulation. Developmental Dynamics 235: 776-785, 2006.
Ware, SM, Harutyunyan, KG, Belmont, JW. Heart defects in X linked heterotaxy: evidence for a genetic interaction of Zic3 with the Nodal signaling pathway. Developmental Dynamics 235:1631-1637, 2006.
Ware, SM. DNA mutation analysis in heterotaxy. Methods Mol Med 126:247-56, 2006.
Bedard, JEJ, Purnell, JD, Ware, SM. Nuclear import and export signals are essential for proper cellular trafficking and function of ZIC3. Human Molecular Genetics 16: 187-198, 2007.
