Identification of two novel variants in homeodomain of MSX1 associated with oligodontia

This study aimed to identify pathogenic variants in two Chinese families with non-syndromic oligodontia and elucidate their functional consequences. Whole-exome sequencing (WES) was performed to screen causal variants in two probands. Bioinformatics tools predicted protein structural alterations, immunofluorescence assessed subcellular localization, and dual-luciferase reporter assays quantified transcriptional activity on BMP4 gene. Two variants (c.601G>A, p.E201K; c.657G>A, p.W219*) in the MSX1 gene were identified. Patients with the nonsense variant tended to have a higher mean number of missing teeth than those with the missense variant (11.3 vs 8.7), although the difference was not statistically significant. Structural modeling revealed disruption of the nonsense variant’s tertiary structure, and immunofluorescence confirmed aberrant cytoplasmic mislocalization of the truncated protein. Both variants reduced MSX1 expression (p<0.01) and impaired BMP4 activation (p<0.05), with the nonsense variant showing greater functional impairment. These findings expand the MSX1 variant spectrum in oligodontia. The results indicate that MSX1 mutations may cause oligodontia through disruption of TGF-β/BMP signaling, advancing our understanding of tooth development mechanisms.