LRP4 mutations, dental anomalies, and oral exostoses.

Background: In order to generate a normal set of teeth, fine‐tuning of Wnt/β‐catenin signaling is required, in which WNT ligands bind to their inhibitors or WNT inhibitors bind to their co‐receptors. Lrp4 regulates the number of teeth and their morphology by modulating Wnt/β‐catenin signaling as a Wnt/β‐catenin activator or inhibitor, depending on its interactions with the partner proteins, such as Sostdc1 and Dkk1. Aim: To investigate genetic etiologies of dental anomalies involving LRP4 in a Thai cohort of 250 children and adults with dental anomalies. Design: Oral and radiographic examinations and whole exome sequencing were performed for every patient. Results: Two novel (p.Leu1356Arg and p.Ala1702Gly) and three recurrent (p.Arg263His, p.Gly1314Ser, and p.Asn1385Ser) rare variants in low‐density lipoprotein receptor‐related protein 4 (LRP4: MIM 604270) were identified in 11 patients. Oral exostoses were observed in five patients. Conclusion: Antagonism of Bmp signaling by Sostdc1 requires the presence of Lrp4. Mice lacking Lrp4 have been demonstrated to have alteration of Wnt–Bmp–Shh signaling and an abnormal number of incisors. Therefore, the LRP4 mutations found in our patients may disrupt Wnt–Bmp–Shh signaling, thereby resulting in dental anomalies and oral exostoses. Root maldevelopment in the patients suggests an important role of LRP4 in root morphogenesis. [ABSTRACT FROM AUTHOR]