Skeletal Class III Malocclusion Is Associated with ADAMTS2 Variants and Reduced Expression in a Familial Case

Area of Science:

• Genetics
• Developmental Biology
• Oral and Maxillofacial Surgery

Background:

• Skeletal Class III malocclusion with maxillary deficiency is a severe condition with poorly understood causes.
• Genetic factors are implicated in craniofacial development disorders.

Purpose of the Study:

• To investigate the genetic basis of skeletal Class III malocclusion with maxillary deficiency in a Han Chinese family.
• To identify specific gene variants contributing to the disease phenotype.

Main Methods:

• Whole exome sequencing was performed on a family diagnosed with the condition.
• In silico prediction tools and cellular assays (HEK293, dental pulp stem cells) were used to assess variant pathogenicity.
• A zebrafish model (adamts2-knockdown) was employed to study craniofacial development.
• Bioinformatic analysis explored downstream signaling pathways.

Main Results:

• A deleterious missense variant, ADAMTS2 (c.3506G>T: p.G1169V), was identified and associated with maxillary deficiency.
• The variant decreased ADAMTS2 expression in cellular models.
• Zebrafish with adamts2 knockdown showed reduced craniofacial bone length and width, with no mandibular changes.
• Sox3 expression was downregulated in knockdown zebrafish, and ErbB signaling was potentially inhibited in human cells.

Conclusions:

• The ADAMTS2 (c.3506G>T: p.G1169V) variant may increase susceptibility to skeletal Class III malocclusion with maxillary deficiency.
• ADAMTS2 plays a role in embryonic craniofacial development and osteogenesis, potentially through the ErbB signaling pathway.