Randomization of Left-Right Asymmetry and Congenital Heart Defects

Nöthe-Menchen, Tabea ; Wallmeier, Julia ; Pennekamp, Petra ; Höben, Inga M. ; Olbrich, Heike ; Loges, Niki T. ; Raidt, Johanna ; Dougherty, Gerard W. ; Hjeij, Rim ; Dworniczak, Bernd ; Omran, Heymut ; Amirav, Israel ; Biebach, Luisa ; Fabricius, Dorit ; Griese, Matthias ; Große-Onnebrink, Jörg ; Häffner, Karsten ; Hector, Andreas ; Jung, Andreas ; Kaiser-Labusch, Petra ; Kaiser, Thomas ; Keßler, Christina ; Kitz, Richard ; Knowles, Michael R. ; Koerner-Rettberg, Cordula ; Kristoffersson, Ulf ; Leigh, Margaret W. ; Mertsch, Pontus ; Mischo, Bernhard ; Nielsen, Kim G.

; Poeta, Marco ; Rietschel, Ernst ; Roth, Samra ; Santamaria, Francesca ; Schmalstieg, Christian ; Schmidts, Miriam ; Schwarz, Carsten ; Schwerk, Nicolaus ; Seithe, Horst ; Tebbe, Johannes ; Werner, Claudius ; Zariwala, Maimoona A.

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Background: Nearly one in 100 live births presents with congenital heart defects (CHD). CHD is frequently associated with laterality defects, such as situs inversus, a mirrored positioning of internal organs. Body laterality is established by a complex process: monocilia at the embryonic left-right organizer facilitate both the generation and sensing of a leftward fluid flow. This induces the conserved left-sided Nodal signaling cascade to initiate asymmetrical organogenesis. Primary ciliary dyskinesia originates from dysfunction of motile cilia, causing symptoms such as chronic sinusitis, bronchiectasis and frequently situs inversus totalis. The most frequently mutated gene in primary ciliary dyskinesia, DNAH5 is associated with randomization of body asymmetry resulting in situs inversus totalis in half of the patients; however, its relation to CHD occurrence in humans has not been investigated in detail so far. Methods: We performed genotype/phenotype correlations in 132 patients with primary ciliary dyskinesia carrying disease-causing DNAH5 mutations, focusing on situs defects and CHD. Using high-speed video microscopy-, immunofluorescence-, and in situ hybridization analyses, we investigated the initial steps of left-right axis establishment in embryos of a Dnah5-mutant mouse model. Results: In patients with primary ciliary dyskinesia carrying disease-causing DNAH5 mutations, 65.9% (87/132) had laterality defects: 88.5% (77/87) presented with situs inversus totalis, 11.5% (10/87) presented with situs ambiguus; and 6.1% (8/132) presented with CHD. In Dnah5(mut/mut) mice, embryonic left-right organizer monocilia lack outer dynein arms resulting in immotile cilia, impaired flow at the left-right organizer, and randomization of Nodal signaling with normal, reversed or bilateral expression of key molecules. Conclusions: For the first time, we directly demonstrate the disease-mechanism of laterality defects linked to DNAH5 deficiency at the molecular level during embryogenesis. We highlight that mutations in DNAH5 are not only associated with classical randomization of left-right body asymmetry but also with severe laterality defects including CHD.

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