ACP4 Variants In Hypoplastic Amelogenesis Imperfecta

Amelogenesis imperfecta (AI) is a group of rare inherited conditions causing tooth enamel defects. Human acid phosphatase 4 (ACP4) is a transmembrane protein involved in maintaining appositional enamel growth. Variants in <em>ACP4</em> cause recessive hypoplastic AI. Here we identify further families and review published <em>ACP4</em> variants causing AI.</p> <p>In three Pakistani families we identified a new <em>ACP4</em> variant, c.254T&thinsp;&gt;&thinsp;C, p.(Pro85Leu), which long-read sequencing revealed to be a founder variant. Two further families were homozygous for previously reported pathogenic <em>ACP4</em> variants. Further details are also reported for two families previously listed in a technical/cohort study by this group. In total seventeen <em>ACP4</em> variants had been reported in the literature causing AI in seventeen families prior to this study. This report adds an eighteenth variant and brings the total to 22 families, suggesting that <em>ACP4</em> variants can be expected to be encountered as a cause of recessive AI, with specific variants more relevant to AI pathogenesis in particular populations.</p> <p> <em>ACP4</em> variants implicated in AI include fifteen missense, one splice and two frame-breaking deletions. Missense variants lie mainly in the acid phosphatase domain, with one in the transmembrane domain. The consistent hypoplastic phenotype suggests a single mutational mechanism, and the report of a family with a homozygous frameshift variant likely to be subject to nonsense mediated decay points to loss of function. Missense variants alter amino acids at the catalytic core or affect protein stability, homodimerisation or membrane localisation, all likely to result in functional insufficiency.