Genes associated with the WNT pathway play an important role in the etiology of tooth agenesis. Low-density lipoprotein receptor–related protein 6 encoding gene ( LRP6) is a recently defined gene that is associated with autosomal dominant inherited tooth agenesis. Here, we aimed to identify novel LRP6 mutations in patients with tooth agenesis and investigate the significance of Lrp6 during tooth development. Using whole-exome sequencing, we identified 4 novel LRP6 heterozygous mutations (c.2292G>A, c.195dup, c.1095dup, and c.1681C>T) in 4 of 77 oligodontia patients. Notably, a patient who carried a nonsense LRP6 mutation (c.2292G>A; p.W764*) presented a hypohidrotic ectodermal dysplasia phenotype. Preliminary functional studies, including bioinformatics analysis and TOP-/FOP-flash reporter assays, demonstrated that the activation of WNT/β-catenin signaling was compromised as a consequence of LRP6 mutations. RNAscope in situ hybridization revealed dynamic and special changes of Lrp6 expression during murine tooth development from E11.5 to E16.5. It was noteworthy that Lrp6 was specifically expressed in the epithelium at E11.5 to E13.5 but was expressed in both dental epithelium and dental papilla from E14.5 and persisted in both tissues at later stages. Our study broadens the mutation spectrum of human tooth agenesis and is the first to identify a LRP6 mutation in patients with hypohidrotic ectodermal dysplasia and reveal the dynamic expression pattern of Lrp6 during tooth development. Information from this study is conducive to understanding the functional significance of Lrp6 on the biological process of tooth development.
A Rare Case of Hypohidrotic Ectodermal Dysplasia Caused by Compound Heterozygous Mutations in the EDAR Gene