Abstract 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 ACP4 cause recessive hypoplastic AI. Here we identify further families and review published ACP4 variants causing AI. In three Pakistani families, we identified a new ACP4 variant, c.254T > C, p.(Pro85Leu), which long-read sequencing revealed to be a founder variant. Two further families were homozygous for previously reported pathogenic ACP4 variants. Further details are also reported for two families previously listed in a technical/cohort study by this group. In total, seventeen ACP4 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. Nine families derive from a cohort of over 400 AI probands curated in Leeds, UK, and account for 9/129 families solved for recessive AI, suggesting ACP4 variants are a significant cause of recessive AI. ACP4 variants implicated in AI include fifteen missense, one splice and two frame-breaking deletions. Most missense variants are within 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.
Liu et al. (Sat,) studied this question.