Orodental malformations associated with human MSX1 sequence variants.

Area of Science:

• Genetics
• Developmental Biology
• Oral Medicine

Background:

• MSX1 gene variants are linked to human tooth agenesis (TA) and orofacial clefts.
• The precise role of MSX1 in tooth development requires further elucidation.
• This study investigates a family with TA and a novel MSX1 variant.

Purpose of the Study:

• To identify the genetic cause of TA in a 4-member family.
• To characterize the phenotypic and molecular consequences of a novel MSX1 variant.
• To understand the role of MSX1 in human tooth and orodental development.

Main Methods:

• Whole exome sequencing to identify the causative variant.
• Microcomputed tomography and morphometric analysis for dental structure evaluation.
• Transcriptome profiling and molecular assays to assess gene function.

Main Results:

• A novel pathogenic MSX1 variant (p.Glu232*) was identified in affected individuals with TA and orodental anomalies.
• Affected teeth exhibited thin dentin and homeotic transformation of mandibular molars.
• Downregulation of extracellular matrix and dentinogenesis genes (DMP1, MMP20) was observed.
• Truncated MSX1 showed impaired transactivation, with variants in the homeobox domain causing more severe phenotypes.

Conclusions:

• MSX1 is crucial for the development of diverse human orodental tissues.
• Specific orodental features like hypertrophic labial frenum and incisor diastema may indicate MSX1-associated TA.