ENAM mutations and digenic inheritance.

Area of Science:

• Genetics
• Oral Biology
• Developmental Biology

Background:

• Amelogenesis imperfecta (AI) is a group of inherited enamel defects.
• ENAM mutations are a known cause of AI, with severity often dose-dependent.
• The role of digenic inheritance in AI is not fully understood.

Purpose of the Study:

• To identify novel mutations in the ENAM gene associated with AI.
• To investigate the potential role of digenic inheritance in AI.
• To characterize enamel phenotypes in a mouse model with combined ENAM and LAMA3 mutations.

Main Methods:

• Whole exome sequencing and Sanger sequencing were used to identify mutations in AI probands.
• Segregation analysis was performed to confirm the link between mutations and AI.
• Enamel phenotype in genetically modified mice (Enam+/- Ambn+/-) was analyzed using scanning electron microscopy.

Main Results:

• Five families showed ENAM mutations segregating with AI, including two novel frameshift mutations.
• One family exhibited a digenic inheritance pattern with both ENAM and LAMA3 mutations.
• Mouse models demonstrated that combined Enam and Ambn heterozygosity resulted in thin, rough enamel with ectopic mineralization and attrition.

Conclusions:

• Novel ENAM mutations causing AI were identified, expanding the known spectrum of ENAM variations.
• The study provides evidence for digenic inheritance contributing to AI severity.
• Digenic inheritance should be considered as a potential cause of AI in human patients.