A Mouse Model Of Primary Ciliary Dyskinesia Reveals High Frequencies Of Heterotaxy And Complex Congenital Heart Defects

Specification of left-right asymmetry is essential for formation of the four chamber heart and separate systemic and pulmonary circulation. Previous studies suggest monocilia at the embryonic node is required for left-right patterning. This patterning is perturbed in primary ciliary dyskinesia (PCD) where situs defects and bronchiectasis are observed, often due to ciliary dysfunction arising from dynein mutations. Most PCD patients exhibit situs solitus or situs inversus totalis, but heterotaxy with complex congenital heart disease (CHD) appears to be rare, reported as 6%. We recovered a mouse mutation in dynein Mdnah5 that disrupts ciliary function. Homozygote mutants exhibit situs phenotypes consistent with PCD in humans. To assess the frequency of CHD associated with PCD, we harvested16 litters of embryos. All wildtype and heterozygous offspring (89) showed normal body situs. Of the 21 (19%) homozygous mutants obtained, 6 had situs solitus, 7 situs inversus and 8 heterotaxy, with heterotaxy being any situs deviation in the cardiac, pulmonary or visceral anatomy. Of the heterotaxic embryos, 3 had levo and 5 dextrocardia. Histology and 3D reconstruction showed 7 of the heterotaxy embryos had complex CHD, which included atrial isomerism, superior-inferior ventricles (Figure ), malposition of the great arteries, AV cushion defects, and azygous continuation of the inferior vena cava. These results show a much higher frequency of heterotaxy and complex CHD than previously reported for PCD (38% vs. 6%), suggesting PCD patients should be screened for CHD. The high incidence of CHD associated with PCD indicates ciliary function may have other roles in cardiovascular patterning.