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Heterotaxy, a disorder in which visceral organs, including the heart, are mispatterned along the left-right body axis, contributes to particularly severe forms of congenital heart disease that are difficult to mitigate even despite surgical advances. A higher incidence of heterotaxy among individuals with blood kinship and the existence of rare monogenic disease forms suggest the existence of a genetic component, but the genetic and phenotypic heterogeneity of the disease have rendered gene discovery challenging. Next generation genomics in patients with syndromic, but also non-syndromic and sporadic heterotaxy, have recently helped to uncover new candidate disease genes, expanding the pool of genes already identified via traditional animal studies. Further characterization of these new genes in animal models has uncovered fascinating mechanisms of left-right axis development. In this review, we will discuss recent findings on the functions of heterotaxy genes with identified patient alleles.
Figure 1. Conserved sequence of LR patterning events in amphibians and mammals. LR patterning steps are depicted in Xenopus, which has been traditionally used in LR patterning studies, and most recently employed to assess functions of novel candidate heterotaxy genes. LR patterning begins at gastrulation, where LRO progenitor cells undergo patterning and morphogenesis. In frog, the LRO derives from superficialmesoderm, which expresses foxj1. Once gastrulation is complete, ciliogenesis ensues in the LRO, which in Xenopus, is a transient teardrop-shaped tissue in the embryoposterior. Ciliogenesis requires a choice between motile and immotile ciliary identity, the physical extension of a cilium, as well as its correct positioning in the posterior of LRO cells. Once ciliogenesis is complete, motile cilia in the LRO center beat in a unidirectional manner generating leftward extracellular fluid flow (red arrows). In the peripheral LRO, immotile cilia are thought to sense this flow, and asymmetric gene expression is first induced in this region: Dand5 (Nodal inhibitor) expression is downregulated as a consequence of fluid flow in the rightLRO, allowing for activation of Nodal signaling solely in the leftLRO. Nodal co-ligands (GDF1, CFC1) potentiate the Nodal signal and increase its range from the LRO to the LPM (marked by pitx2c expression). Several factors can further modulate Nodal expression in the LPM, including BMPs and FGFs. Asymmetric expression of LR cues in the LPM is instructive for asymmetric organogenesis, but factors involved in establishing the physical asymmetries of different organs per se (e.g. bending of the cardiac tube) remain largely unassociated to human heterotaxy up-to-date. A tadpole is shown during organogenesis stages, with the cardiac outflow tract looping to the right (pseudocolored in pink), counter-clockwise gut looping (dotted line) and right-sided gall-bladder (pseudocolored green).
