WNT10A-SMOC2-LRP4 network affects permanent tooth development via potential tooth-bone interaction

Permanent tooth loss is a key feature of non-syndromic tooth agenesis (NSTA). However, whether this is influenced by the mandibular environment remains unclear. We report a case of simultaneous variations in the tooth agenesis-associated genes WNT10A and SMOC2 and the bone formation-associated gene LRP4, exploring the potential impact of the mandibular environment on tooth agenesis.

A 19-year-old patient with NSTA underwent clinical examination and genetic analysis using whole-exome sequencing and Sanger sequencing. We reanalyzed single-cell RNA-seq datasets from human molars and surrounding tissues and performed immunofluorescent staining on key cell subsets.

The patient exhibited significant retention of primary teeth and loss of nine permanent teeth, with cone-beam computed tomography(CBCT) showing increased bone density and structural abnormalities. Genetic analysis revealed a novel variation in LRP4 (c.1831 C > T, p.R611C), and variations in SMOC2 (c.1138 C > T, p.R380C) and WNT10A (c.354T > G, p.Y118*). Protein structure analysis revealed differences in the RMSD and hydrogen bonds between mutated LRP4 and SMOC2. Additionally, LRP4-positive alveolar bone cells send Fibroblast Growth Factor (FGF) signals to WNT10A-positive and SMOC2-positive dental pulp cells.

Based on a case of NSTA with SMOC2 and novel LRP4 variations linked to tooth agenesis and bone development, we revealed that LRP4 + alveolar bone cells may influence tooth development through FGF signaling, thereby regulating WNT10A + and SMOC2 + dental pulp cells.