Investigation of a Novel Variant Causing Autosomal-Dominant Tooth Agenesis.

Background: The low-density lipoprotein receptor-related protein 6 () gene is a recently defined gene that is associated with the autosomal-dominant inherited tooth agenesis (TA). In the present study, a family of four generations having TA was recruited and subjected to a series of clinical, genetic, , and investigations.

Methods: After routine clinical evaluation, the proband was subjected to whole-exome sequencing (WES) to detect the diagnostic variant. Next, structural and molecular dynamics (MD) analysis was conducted on the identified novel missense variant for predicting its intramolecular impact. Subsequently, an study was performed to further explore the effect of this variant on protein maturation and phosphorylation.

Results: WES identified a novel variant, designated as : c.2570G > A (p.R857H), harbored by six members of the concerned family, four of whom exhibited varied TA symptoms. The analysis suggested that this novel variant could probably damage the Wnt bonding function of the LRP6 protein. The experimental study demonstrated that although this novel variant did not affect the gene transcription, it caused a impairment in the maturation and phosphorylation of LRP6 protein, suggesting the possibility of the disruption of the Wnt signaling.

Conclusion: The present study expanded the mutation spectrum of human TA in the gene. The findings of the present study are insightful and conducive to understanding the functional significance of specific variants.