A mouse model of conduction system patterning abnormalities in heterotaxy syndrome

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Pediatric Research (Impact Factor: 2.31). 10/2010; 68(4):275-80. DOI: 10.1203/PDR.0b013e3181ee0028
Source: PubMed


Duplication or absence of parts of the specialized cardiac conduction system in patients with heterotaxy syndrome causes significant clinical disease, but the mechanistic basis by which embryonic disruption of left-right patterning alters conduction system patterning in these patients is not well understood. We sought to determine whether a mouse model of X-linked human heterotaxy recapitulates conduction system abnormalities identified in patients with heterotaxy. Cardiac structure and conduction system patterning were evaluated in Zic3 null embryos from e9.5 to e16.5 using genetic and molecular methods. Severe structural abnormalities involving atrial, ventricular, and conotruncal development were associated with a spectrum of disorganized and ambiguous arrangements throughout the conduction system, including the appearance of duplicated structures. The severity and location of conduction system abnormalities correlated with the severity and location of associated structural heart disease and were identifiable at the earliest stages examined. The Zic3 mouse model provides a novel tool to dissect the mechanistic underpinnings of conduction system patterning and dysfunction and its relationship to cardiovascular malformations, making it a promising model to improve understanding and risk assessment in the clinical arena.

Download full-text


Available from: Stephanie M Ware, Sep 30, 2015
25 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with heterotaxy have characteristic cardiovascular malformations, abnormal arrangement of their visceral organs, and midline patterning defects that result from abnormal left-right patterning during embryogenesis. Loss of function of the transcription factor ZIC3 causes X-linked heterotaxy and isolated congenital heart malformations and represents one of the few known monogenic causes of congenital heart disease. The birth incidence of heterotaxy-spectrum malformations is significantly higher in males, but our previous work indicated that mutations within ZIC3 did not account for the male over-representation. Therefore, cross species comparative sequence alignment was used to identify a putative novel fourth exon, and the existence of a novel alternatively spliced transcript was confirmed by amplification from murine embryonic RNA and subsequent sequencing. This transcript, termed Zic3-B, encompasses exons 1, 2, and 4 whereas Zic3-A encompasses exons 1, 2, and 3. The resulting protein isoforms are 466 and 456 amino acid residues respectively, sharing the first 407 residues. Importantly, the last two amino acids in the fifth zinc finger DNA binding domain are altered in the Zic3-B isoform, indicating a potential functional difference that was further evaluated by expression, subcellular localization, and transactivation analyses. The temporo-spatial expression pattern of Zic3-B overlaps with Zic3-A in vivo, and both isoforms are localized to the nucleus in vitro. Both isoforms can transcriptionally activate a Gli binding site reporter, but only ZIC3-A synergistically activates upon co-transfection with Gli3, suggesting that the isoforms are functionally distinct. Screening 109 familial and sporadic male heterotaxy cases did not identify pathogenic mutations in the newly identified fourth exon and larger studies are necessary to establish the importance of the novel isoform in human disease.
    PLoS ONE 08/2011; 6(8):e23755. DOI:10.1371/journal.pone.0023755 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Heterotaxy syndrome affects the sidedness of heart, lungs, and abdominal viscera, and is associated with complex congenital heart disease. Cardiac sidedness is defined by the position of the morphological right atrium and may be normal, mirror-image, or isomeric. The sinus node has been reported to be present bilaterally in right isomerism and absent bilaterally in left isomerism, although exceptions may occur. Our aim was to evaluate bilaterally the presence or absence of sinus node tissue in autopsy-derived hearts from patients with heterotaxy and to correlate the findings with the sidedness of the two atria. Autopsy and clinical records were reviewed from 41 cases with heterotaxy. From the cardiac specimens, tissue was collected bilaterally from expected sinus node sites. Sinus node tissue was categorized microscopically as normal, hypoplastic, indeterminate, or absent. In hearts thought to show right atrial isomerism, sinus node tissue was detected bilaterally in 54%, was absent on one side in 43%, and was absent on both sides in 3%. For cases with apparent left atrial isomerism, a single sinus node was present in the left-sided atrium in 75% of cases and was absent bilaterally in 25%. Bilateral sinus nodes were observed in only 54% of cases with right isomerism, and bilateral absence of sinus nodes was documented in only 25% of cases with left isomerism. Thus, our findings indicate that the sinus node is not a morphologically right-sided structure, and its presence therefore is not consistently related to the sidedness of the atria.
    Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 01/2012; 21(5):421-7. DOI:10.1016/j.carpath.2011.12.007 · 2.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The position or location of the organs and vessels is usually classified into three types: situs solitus, situs inversus, and situs ambigus. Situs solitus is the usual arrangement of organs and vessels within the body. Only 0.6 to 0.8% of patients with situs solitus and levocardia have associated congenital heart diseases. Situs inversus refers to an anatomic arrangement that is the mirror image of situs solitus. The incidence of congenital heart disease is increased to 3 to 5% in the patients with situs inversus. The patients with heterotaxy have congenital heart disease in high incidence, ranging from 50 to nearly 100%. We present four cases diagnosed in our department in a period of 18 months. With these four cases and a review in the literature, we explore the definitions and characteristics of heterotaxy syndromes and we study the role of 3D ultrasound.
    Journal de Gynécologie Obstétrique et Biologie de la Reproduction 09/2012; 41(5):489–496. DOI:10.1016/j.jgyn.2012.04.015 · 0.56 Impact Factor
Show more