Mutations in RELT cause autosomal recessive amelogenesis imperfecta

Area of Science:

• Genetics
• Developmental Biology
• Dentistry

Background:

• Amelogenesis Imperfecta (AI) encompasses inherited disorders affecting dental enamel.
• AI can be isolated or part of syndromic conditions.
• The genetic basis for many AI cases remains unknown.

Purpose of the Study:

• To identify the genetic cause of a specific form of autosomal recessive Amelogenesis Imperfecta.
• To investigate the role of the identified gene in enamel formation.
• To explore potential syndromic features associated with the genetic defect.

Main Methods:

• Characterization of three consanguineous families with hypoplastic Amelogenesis Imperfecta.
• Whole-exome sequencing to identify causative mutations.
• RNAscope in situ hybridization in mouse models.
• Generation and analysis of Relt knockout mice (Relt-/-) using CRISPR/Cas9.
• Phylogenetic analysis of the RELT gene.

Main Results:

• Homozygous loss-of-function mutations in the novel gene RELT (Tumor Necrosis Factor Receptor Superfamily member) were identified in all affected individuals.
• RELT is specifically expressed in ameloblasts and odontoblasts during the secretory stage of tooth development.
• Relt-/- mice exhibit enamel hypoplasia, surface defects, and rapid attrition.
• Abnormal mineralization at the dentino-enamel junction (DEJ) was observed in Relt-/- mice.
• Phylogenetic analysis suggests evolutionary pressure on RELT outside of tooth development.

Conclusions:

• Mutations in RELT cause a distinct form of Amelogenesis Imperfecta.
• RELT plays a critical role in enamel matrix formation and mineralization during the secretory stage.
• The findings suggest that AI associated with RELT mutations may present with syndromic features, including impaired growth and immune deficiencies.
• This study expands the known genetic causes of Amelogenesis Imperfecta and provides insights into enamel development.