Ascl5 variant disrupts gene expression in developing mandibular teeth and dental arch structures

ABSTRACT: Lobodontia, a rare dental anomaly marked by supernumerary cusps and a single pyramid-shaped molar root resembling carnivorous teeth, is s linked to variants in the CACNA1S gene. However, the underlying molecular mechanisms remain unclear. Here, we identified a novel heterozygous missense variant in ASCL5 (c.274G>A, p.Glu92Lys) as the primary genetic determinant for lobodontia. Through microsatellite linkage and genome sequencing analysis of six families affected by lobodontia, we identified the ASCL5 c.274G>A variant, located upstream of the previously reported CACNA1S variant, completely segregating with the phenotype. To validate this finding, we generated Ascl5 knock-in mutant mice using CRISPR/Cas9. Ascl5Mut/WT exhibited dental anomalies resembling human lobodontia, while Ascl5Mut/Mut displayed significant defects in tooth and jaw development, underscoring the essential role of ASCL5 in craniofacial patterning. Transcriptomic analysis of E17.5 mandibular teeth and arches revealed a significant differential expression of forty-two genes in Ascl5mut/mut compared to Ascl5WT/WT, including reduced expression of key developmental genes Dlx1as, Dlx2, and Shh. Functional assays showed that ASCL5 promotes transcriptional activity of DLX2, a key regulator of craniofacial development. However, the p.Glu92Lys ASCL5 significantly impaired this activation, providing a mechanistic explanation for the observed phenotype. This study establishes ASCL5 as the primary gene responsible for lobodontia, revising the previously understood genetic basis of this rare condition. Our findings highlight the crucial role of ASCL5 in craniofacial development, opening new avenues for understanding craniofacial anomalies.

ORGANISM(S): Mus musculus

PROVIDER: GSE279607 | GEO | 2025/12/07

REPOSITORIES: GEO