A missense variant in ASCL5 leads to lobodontia

Area of Science:

• Genetics
• Developmental Biology
• Oral Pathology

Background:

• Lobodontia is a rare dental anomaly characterized by extra cusps and a single, pyramid-shaped molar root.
• Previous research suggested a link to a CACNA1S gene variant, but evidence was inconclusive.

Purpose of the Study:

• To identify the genetic basis of lobodontia.
• To investigate the role of ASCL5 in craniofacial development.

Main Methods:

• Microsatellite genotyping and whole-genome sequencing were performed on affected families.
• CRISPR/Cas9 technology was used to create Ascl5 mutant mice for functional studies.
• Transcriptomic analysis and luciferase assays were conducted to assess gene function.

Main Results:

• All 17 lobodontia patients carried the ASCL5 c.274G>A (p.Glu92Lys) variant, absent in unaffected individuals.
• Ascl5 mutant mice exhibited dental anomalies and craniofacial defects, confirming ASCL5's essential role.
• The p.Glu92Lys variant impaired DLX2 activation, indicating pathogenicity.

Conclusions:

• ASCL5 is the causative gene for lobodontia, revising its known genetic etiology.
• ASCL5 plays a critical role in mammalian craniofacial patterning and tooth development.
• The identified ASCL5 variant provides a molecular explanation for this rare dental anomaly.