Genotypic-Phenotypic Comparisons of Two AMELX Deletions

Amelogenesis imperfecta (AI) is a group of inherited conditions featuring isolated enamel malformations. About 10% of AI cases show an X-linked pattern of inheritance. The enamel protein amelogenin is encoded by AMELX (Xp22.3) and AMELY (Yp11.2). About 90% of amelogenin expression is from AMELX, which is nested within intron 1 of the gene encoding Rho GTPase activating protein 6 (ARHGAP6). We identified two AI families with deletions in ARHGAP6.

Objectives: To characterize the phenotype of two families with hypoplastic AI and identify their causative genetic mutations.

Methods: After demonstrated that none of the AMELX coding exons could be amplified, we continued to amplify nearby regions of Xp22.3 to define the deleted segments by chromosomal walking. Clinical phenotypes were characterized based on dental examinations, photographs and radiographs.

Results: Family 1 had a 52,654 bp deletion starting in intron 1 and ending in intron 2 of ARHGAP6, including all of AMELX and exon 2 (160 bp) of ARHGAP6. Deleting exon 2 shifts the reading frame of ARHGAP6 mRNA transcripts. Family 2 had a smaller deletion including all of AMELX, but was limited to intron 1 of ARHGAP6. The enamel defects were similar in the two families, but showed wide variations within and between affected individuals. A male primary dentition displayed generally thin enamel, as did the permanent teeth of a female carrier. The permanent teeth of affected males were rough and stained to varying degrees. The enamel was whiter on the incisal edges of anterior teeth and the cusp tips of posterior teeth.

Conclusion: Enamel malformations have a similar appearance when AMELX alone or with exon 2 of ARHGAP6 is deleted. If exon 2 is critical for ARHGAP6 function, its deletions do not appreciably alter the severity of enamel defects when AMELX is absent. This study was supported by NIDCR grant DE015846.