A NOVEL Mutation in Eda Causes X-Linked Recessive Tooth Agenesis

Identification of the genes responsible for syndromic and non-syndromic forms of tooth agenesis is central to our understanding of the molecular mechanisms underlying normal and abnormal tooth development.

Objective: To identify the causative gene and mutation that is responsible for an X-linked recessive form of non-syndromic tooth agenesis in a multigenerational family.

Methods: Informed consent and DNA samples were obtained according to HIPAA and IRB protocols. Pedigree analysis revealed an X-linked recessive mode of inheritance, directing our attention to the EDA gene (Xq12-13.1). Eight exons of the EDA gene were PCR amplified using DNA from the index male followed by fluorescence-based sequencing. DNA of other family members and 79 unaffected controls was investigated by restriction fragment length polymorphism (RFLP).

Results: DNA sequencing revealed a T to C transition in the last exon of the EDA gene, at a position corresponding to nucleotide 1336 of the mRNA,. This results in an amino acid change from Valine to Alanine in a highly conserved region of the protein's C-terminal (TNF) domain. The mutation creates a restriction enzyme Hha1 site which allowed mutation detection by RFLP analysis in the remaining study participants: All affected males revealed a mutated copy, female carriers had one mutated and one wild-type (WT) copy and unaffected family members had only WT copies. The mutation was not found in 65 unrelated females and 14 unrelated males. All affected members of this family present with missing primary and permanent incisors with a few individuals reporting sparse hair and no other classical ectodermal dysplasia symptoms.

Conclusions: The presence of tooth agenesis with mild symptoms of ectodermal dysplasia suggests that this novel mutation within the C-terminal domain of the EDA gene has partial effects on its binding to the EDA receptor. Supported by the Baylor Oral health Foundation (RS); NIH U24-PEI6472 (RDS).