Purandare, S.M. et al. A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Development 129, 2293-2302
Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA. Development
(Impact Factor: 6.46).
X-linked heterotaxy (HTX1) is a rare developmental disorder characterized by disturbances in embryonic laterality and other midline developmental field defects. HTX1 results from mutations in ZIC3, a member of the GLI transcription factor superfamily. A targeted deletion of the murine Zic3 locus has been created to investigate its function and interactions with other molecular components of the left-right axis pathway. Embryonic lethality is seen in approximately 50% of null mice with an additional 30% lethality in the perinatal period. Null embryos have defects in turning, cardiac development and neural tube closure. Malformations in live born null mice include complex congenital heart defects, pulmonary reversal or isomerism, CNS defects and vertebral/rib anomalies. Investigation of nodal expression in Zic3-deficient mice indicates that, although nodal is initially expressed symmetrically in the node, there is failure to maintain expression and to shift to asymmetric expression. Subsequent nodal and Pitx2 expression in the lateral plate mesoderm in these mice is randomized, indicating that Zic3 acts upstream of these genes in the determination of left-right asymmetry. The phenotype of these mice correctly models the defects found in human HTX1 and indicates an important role for Zic3 in both left-right and axial patterning.
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- "Agenesis of the corpus callosum, holoprosencephaly, myelomeningocele, and neural tube defects have been reported4546. Such associations were also found in the mouse model of heterotaxy. Discussion of these abnormalities is beyond the scope of our review. "
Available from: Stephanie M Ware
- "Both the complexity of ZIC3-associated phenotypes and its broad expression during embryogenesis [McMahon and Merzdorf, 2010; Nagai et al., 1997; Quinn et al., 2012] are indicative of diversity in ZIC3 developmental function, including recognized roles in neural and neural crest development [Nakata et al., 1997; Klootwijk et al., 2000], limb bud digitation [Quinn et al., 2012], cardiac morphogenesis , and L–R patterning [Jiang et al., 2013; Kitaguchi et al., 2000; Purandare et al., 2002; Sutherland et al., 2013; Ware et al., 2004, 2006a, 2006b; Zhu et al., 2007a, 2007b]. Studies utilizing Zic3-null mice suggest that Zic3 is required for progression into and through gastrulation [Ware et al., 2006a; Cast et al., 2012] and that it acts upstream of Nodal signaling at the embryonic node [Purandare et al., 2002; Ware et al., 2006b]. "
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ABSTRACT: Mutations in zinc-finger in cerebellum 3 (ZIC3) result in heterotaxy or isolated congenital heart disease (CHD). The majority of reported mutations cluster in zinc-finger domains. We previously demonstrated that many of these lead to aberrant ZIC3 subcellular trafficking. A relative paucity of N- and C-terminal mutations has, however, prevented similar analyses in these regions. Notably, an N-terminal polyalanine expansion was recently identified in a patient with VACTERL, suggesting a potentially distinct function for this domain. Here, we report ZIC3 sequencing results from 440 unrelated patients with heterotaxy and CHD, the largest cohort yet examined. Variants were identified in 5.2% of sporadic male cases. This rate exceeds previous estimates of 1% and has important clinical implications for genetic testing and risk-based counseling. Eight of 11 were novel, including 5 N-terminal variants. Subsequent functional analyses included 4 additional reported but untested variants. Aberrant cytoplasmic localization and decreased luciferase transactivation were observed for all zinc-finger variants, but not for downstream or in-frame upstream variants, including both analyzed polyalanine expansions. Collectively, these results expand the ZIC3 mutational spectrum, support a higher than expected prevalence in sporadic cases, and suggest alternative functions for terminal mutations, highlighting a need for further study of these domains. This article is protected by copyright. All rights reserved.
Available from: Helen Bellchambers
- "The katun allele arose as a spontaneous, X-linked mutation during an N-ethyl-N-nitrosourea (ENU) mutagenesis experiment (Bogani et al., 2004), indicating that it might be a new allele of Zic3, the gene deleted in the classical, X-linked mouse mutant bent tail (Bn) (Carrel et al., 2000; Klootwijk et al., 2000) and mutated in targeted mouse strains (Purandare et al., 2002; Zhu et al., 2007). The coding region of Zic3 was amplified from the genomic DNA of a heterozygous female, a hemizygous male, a C3H mouse and a BALB/c mouse and sequenced. "
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ABSTRACT: The ZIC transcription factors are key mediators of embryonic development and ZIC3 is the gene most commonly associated with situs defects (Heterotaxy) in humans. Half of patient ZIC3 mutations introduce a premature termination codon (PTC). In vivo, PTC-containing transcripts may be targeted for nonsense mediated decay (NMD). NMD efficiency is known to vary greatly between transcripts, tissues and individuals and it is possible that differences in survival of PTC-containing transcripts partially explain the striking phenotypic variability that characterizes ZIC3-associated congenital defects. For example the PTC-containing transcripts may encode a C-terminally truncated protein which retains partial function or which dominantly interferes with other ZIC family members. Here we describe the katun (Ka) mouse mutant which harbours a mutation in the Zic3 gene that results in a PTC. At the time of axis formation there is no discernible decrease in this PTC-containing transcript in vivo indicating that the mammalian Zic3 transcript is relatively insensitive to NMD, prompting the need to re-examine the molecular function of the truncated proteins predicted from human studies and to determine whether the N-terminal portion of ZIC3 possesses dominant-negative capabilities. A combination of in vitro studies and analysis of the Ka phenotype indicate it is a null allele of Zic3 and that the N-terminal portion of ZIC3 does not encode a dominant-negative molecule. Heterotaxy in patients with PTC-containing ZIC3 transcripts therefore arises due to loss of ZIC3 function alone.
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