Mutations in the EDA-pathway genes EDA, EDAR and EDARADD lead to the syndrome Hypohidrotic Ectodermal Dysplasia (HED) featuring dysplasia of hair, sweat glands and teeth. Unexpectedly, several EDA and one EDARADD mutation have recently been found among patients with non-syndromic hypodontia. This is of significance for dentists because of the emergence of molecular therapeutics for EDA associated disorders. In order to determine the prevalence of EDA-pathway mutations in non-syndromic tooth agenesis, we performed an EDA-pathway mutation screen in 95 unrelated individuals with non-syndromic tooth agenesis.
DNA was isolated from cheek swabs or saliva samples from 95 unrelated probands who participated in our IRB approved “missing tooth” study. All exons of the EDA, EDAR and EDARADD genes were PCR amplified and sequenced.
No mutations were found in EDARADD.
One possibly causative mutation was found in the EDA gene; it was a 9 bp repeat in intron 7; 26 bp 5’ of the intron7/exon8 border. Upon close examination, the phenotype of the affected male with this mutation showed features of a mild syndromic form of HED rather than isolated hypodontia. In the EDAR gene we found one heterozygous missense mutation in exon 5, changing amino acid 105 from glycine to glutamic acid (Gly105Glu). The phenotype featured a missing maxillary lateral incisor in both primary and permanent dentition. The mother was also affected. Another EDAR mutation was a heterozygous 5 bp deletion in exon 6; the patient was missing both lower second premolars.
Some autosomal dominant EDAR mutations can cause mild selective tooth agenesis. Since most HED-causing mutations in EDAR are autosomal recessive and the few autosomal dominant HED-causing mutations have been described to be dominant negative, prohibiting trimerization of the EDAR proteins, it is conceivable that the non-dominant negative, heterozygous mutations cause only minor hypodontia.
Keywords: Genetics, Nucleic acids and Tooth Agenesis