Human genes for dental anomalies.

The development of the tooth at gene level is beginning to be understood. This paper reviews current knowledge and the advances in research on human genes whose defect leads to dental anomalies. Amelogenesis imperfecta (AI) is a diverse group of hereditary disorders characterized by a variety of developmental enamel defects including hypoplasia and hypomineralization, some of which have been revealed to be associated with defective amelogenin genes. The human amelogenin genes on X and Y chromosomes have been cloned and investigated extensively. Although autosomally inherited forms of AI are more common than the X-linked forms, most studies on the genes causing AI have been performed on the genes of X-linked forms. Recently, the gene for the human tuftelin protein (an enamelin) has been cloned as a candidate gene for the autosomal forms of AI with another gene on chromosome 4 involved in some families. Dentinogenesis imperfecta (DI) may be associated with osteogenesis imperfecta (OI), which is an autosomal dominant bone disease. Most patients with OI have mutations in either the COLIA1 or COLIA2 genes, which encode the alpha 1(I) or alpha 2(I) subunits of type I collagen, the major organic component of bone and dentin. Gene defects causing isolated DI have not been identified. Recently, it was demonstrated that a missense mutation of MSXI, a human homeobox gene, causes autosomal dominant agenesis of second premolars and third molars. Data indicating an important function for MSXI, the mouse counterpart of the human MSXI gene, in mouse tooth development have been accumulating since 1991. Knockout mice lacking this gene exhibited multiple craniofacial anomalies including complete tooth agenesis. X-linked anhidrotic ectodermal dysplasia (EDA), characterized by abnormal hair, teeth, and sweat glands, was demonstrated to be caused by a mutation in a novel transmembrane protein gene that is expressed in epithelial cells and in other adult and fetal tissues. The predicted EDA protein may belong to a novel class of proteins with a role in epithelial-mesenchymal signaling. Several mutations have been reported in genes causing hypophosphatasia, which is characterized by defective mineralization of the skeletal and dental structures.