Exclusion of candidate genes in two families with autosomal dominant hypocalcified amelogenesis imperfecta

The amelogenesis imperfectas (AI) are a group of hereditary enamel defects characterized by clinical and genetic diversity. The most common AI types are inherited as autosomal traits. Three mutations of the enamelin (ENAM ) gene have been found in cases of autosomal dominant hypoplastic AI. The gene(s) responsible for hypocalcified forms of AI have not been identified, although a number of autosomal genes have been proposed as candidates for AI based on their expression by ameloblasts, including ameloblastin and enamelin (chromosome 4q13.3), tuftelin (chromosome 1q21), enamelysin (chromosome 11q22.3-q23) and kallikrein 4 (chromosome 19q13.3-q13.4). To localize the gene(s) responsible for autosomal dominant hypocalcified AI, we evaluated support for/against linkage of AI to genetic markers spanning five AI candidate genes in two extended families. Our data excluded all proposed candidate gene regions as causal for autosomal dominant hypocalcified AI in these families. These linkage findings provide further evidence for genetic heterogeneity among families with autosomal dominant AI and indicate that, at least, some forms of autosomal dominant hypocalcified AI are not caused by a gene in the five most commonly reported AI candidate genes.