Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia
Serena Y. Tan, … , Linda Leatherbury, Cecilia W. Lo
Serena Y. Tan, … , Linda Leatherbury, Cecilia W. Lo
Published November 21, 2007
Citation Information: J Clin Invest. 2007;117(12):3742-3752. https://doi.org/10.1172/JCI33284.
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Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder associated with ciliary defects and situs inversus totalis, the complete mirror image reversal of internal organ situs (positioning). A variable incidence of heterotaxy, or irregular organ situs, also has been reported in PCD patients, but it is not known whether this is elicited by the PCD-causing genetic lesion. We studied a mouse model of PCD with a recessive mutation in Dnahc5, a dynein gene commonly mutated in PCD. Analysis of homozygous mutant embryos from 18 litters yielded 25% with normal organ situs, 35% with situs inversus totalis, and 40% with heterotaxy. Embryos with heterotaxy had complex structural heart defects that included discordant atrioventricular and ventricular outflow situs and atrial/pulmonary isomerisms. Variable combinations of a distinct set of cardiovascular anomalies were observed, including superior-inferior ventricles, great artery alignment defects, and interrupted inferior vena cava with azygos continuation. The surprisingly high incidence of heterotaxy led us to evaluate the diagnosis of PCD. PCD was confirmed by EM, which revealed missing outer dynein arms in the respiratory cilia. Ciliary dyskinesia was observed by videomicroscopy. These findings show that Dnahc5 is required for the specification of left-right asymmetry and suggest that the PCD-causing Dnahc5 mutation may also be associated with heterotaxy.

Authors

Serena Y. Tan, Julie Rosenthal, Xiao-Qing Zhao, Richard J. Francis, Bishwanath Chatterjee, Steven L. Sabol, Kaari L. Linask, Luciann Bracero, Patricia S. Connelly, Mathew P. Daniels, Qing Yu, Heymut Omran, Linda Leatherbury, Cecilia W. Lo

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Figure 5

Superior-inferior ventricles and AV canal defect.

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Superior-inferior ventricles and AV canal defect. (A) Superior-inferior ...
(A) Superior-inferior ventricles with congested superior ventricle and atrial appendages with Ao and PA side by side. Note this same heart is shown in different views in Figure 4. (B) 3D model shows mLV is inferior and right-sided, while the mRV is superior and left-sided. (C) 3D reconstruction in an apical orientation looking anteriorly at 2 papillary muscles in the smaller, inferior mLV, as indicated by the 2 arrowheads. There is also a small, muscular VSD present near the apex. (D) Anterior view shows a larger, superior mRV with the septomarginalis (M) between the superior ventricular outflow tract and the body of the right ventricle. The aortic and pulmonic valves (AV and PV) both arise from the mRV, giving rise to a DORV with a VSD. The arrowhead indicates the AV canal defect. (E) Anterior view of 3D EFIC reconstruction illustrates side-by-side, semilunar valves of similar height associated with DORV. The bicuspid aortic valve (AV) is on the left, and the tricuspid pulmonic valve (PV) is on the right. An AV canal defect (AVC) is situated at the crux of the heart. (F) Frontal 2D section showing the same AVC as in E entering both the mRV and the mLV, with a VSD denoted by the arrow. LA, left atrium. Scale bars: 500 μm.