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Abstract

We thank Dr Reich for his interest and comments on our recent article in CHEST.1Shapiro AJ Davis SD Ferkol T et al.On behalf of the Genetic Disorders of Mucociliary Clearance Consortium. Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy.Chest. 2014; 146: 1176-1186Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar The link between motile cilia and organ laterality defects has been firmly established since Nonaka and colleagues2Nonaka S Tanaka Y Okada Y et al.Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein.Cell. 1998; 95: 829-837Abstract Full Text Full Text PDF PubMed Scopus (1254) Google Scholar first described this in mice with dysfunction of embryonic nodal cilia. Since then, several heterotaxy mouse models have confirmed the association of dynein arm defects and embryonic nodal cilia dysmotility with primary ciliary dyskinesia (PCD).3Tan SY Rosenthal J Zhao XQ et al.Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia.J Clin Invest. 2007; 117: 3742-3752PubMed Google Scholar, 4Francis RJ Christopher A Devine WA Ostrowski L Lo C Congenital heart disease and the specification of left-right asymmetry.Am J Physiol Heart Circ Physiol. 2012; 302: H2102-H2111Crossref PubMed Scopus (39) Google Scholar, 5Lucas JS Adam EC Goggin PM et al.Static respiratory cilia associated with mutations in Dnahc11/DNAH11: a mouse model of PCD.Hum Mutat. 2012; 33: 495-503Crossref PubMed Scopus (49) Google ScholarTheories on the interactions between motile nodal cilia and various forms of nonmotile cilia, both in the embryonic node6McGrath J Somlo S Makova S Tian X Brueckner M Two populations of node monocilia initiate left-right asymmetry in the mouse.Cell. 2003; 114: 61-73Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar and in the developing heart itself,7Slough J Cooney L Brueckner M Monocilia in the embryonic mouse heart suggest a direct role for cilia in cardiac morphogenesis.Dev Dyn. 2008; 237: 2304-2314Crossref PubMed Scopus (75) Google Scholar have suggested that various signaling pathways are required for embryonic heart and visceral organ formation. Some of these signaling pathways may rely on nonmotile cilia8Koefoed K Veland IR Pedersen LB Larsen LA Christensen ST Cilia and coordination of signaling networks during heart development.Organogenesis. 2014; 10: 108-125Crossref PubMed Scopus (57) Google Scholar or even mechanosensory functions9Shah AS Ben-Shahar Y Moninger TO Kline JN Welsh MJ Motile cilia of human airway epithelia are chemosensory.Science. 2009; 325: 1131-1134Crossref PubMed Scopus (527) Google Scholar of motile cilia. However, thus far in human studies, genetic mutations causing PCD with organ laterality defects are limited to those encoding for dynein arms, which are also required for embryonic nodal cilia motility.1Shapiro AJ Davis SD Ferkol T et al.On behalf of the Genetic Disorders of Mucociliary Clearance Consortium. Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy.Chest. 2014; 146: 1176-1186Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Human studies have failed to demonstrate PCD with cardiac defects or organ laterality defects involving deformities of the central apparatus or radial spokes (which are normally absent in embryonic nodal cilia). Of note, laterality defects have been seen in several primary ciliopathies including Bardet-Biedl syndrome, Meckel syndrome, nephronophthisis, and Jeune syndrome,10Tobin JL Beales PL The nonmotile ciliopathies.Genet Med. 2009; 11: 386-402Crossref PubMed Scopus (153) Google Scholar supporting the concept that sensory cilia play a role in organ laterality. Although we are merely beginning to understand the complex interplay between motile and nonmotile cilia in congenital heart disease and organ laterality defects, we can only confirm aberrations in motile cilia as directly causing PCD with organ laterality defects.