Nodal Pathway Genes Are Down-regulated in Facial Asymmetry

Purpose: Facial asymmetry is a common comorbid condition in patients with jaw deformation malocclusion. Heritability of malocclusion is advancing rapidly, but very little is known regarding genetic contributions to asymmetry. This study identifies differences in expression of key asymmetry-producing genes that are down-regulated in patients with facial asymmetry. Methods: Masseter muscle samples were collected during bilateral sagittal split osteotomy orthognathic surgery to correct skeletal-based malocclusion. Patients were classified as class II or III and open or deep bite malocclusion with or without facial asymmetry. Muscle samples were analyzed for gene expression differences on Affymetrix HT2.0 microarray global expression chips. Results: Overall gene expression was different for asymmetric patients compared with other malocclusion classifications by principal component analysis (P < 0.05). We identified differences in the nodal signaling pathway, which promotes development of mesoderm and endoderm and left-right patterning during embryogenesis. Nodal and Lefty expression was 1.39- to 1.84-fold greater (P < 3.41 x 10(-5)), whereas integral membrane Nodal modulators Nomo1,2,3 were -5.63 to -5.81 (P < 3.05 x 10(-4)) less in asymmetry subjects. Fold differences among intracellular pathway members were negative in the range of -7.02 to -2.47 (P < 0.003). Finally Pitx2, an upstream effector of Nodal known to influence the size of type II skeletal muscle fibers was also significantly decreased in facial asymmetry (P < 0.05). Conclusions: When facial asymmetry is part of skeletal malocclusion, there are decreases in nodal signaling pathway genes in masseter muscle. This data suggest that the nodal signaling pathway is down-regulated to help promote development of asymmetry. Pitx2 expression differences also contributed to both skeletal and muscle development in this condition.