Genetic Mechanisms of Amelogenesis Imperfecta

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Amelogenesis imperfecta (AI) is a diverse collection of about 90 inherited conditions all manifesting enamel malformations, and each caused by defects in a different gene. Many AI cases are isolated (only exhibit enamel defects). Others are syndromic. The syndromes can involve very serious health problems, including blindness, kidney calcifications, immunodeficiency, skin fragility, epilepsy, etc. Primary teeth start to erupt at 6 months so enamel defects are often an early sign of a larger disease, and the only apparent phenotype at the time of diagnosis. As some systemic conditions can be mitigated by early medical intervention, an early and accurate diagnosis can minimize the effects of the condition on the patient's health. Without an accurate genetic diagnosis, early intervention to mitigate pending systemic deterioration cannot be employed. A barrier to making a genetic diagnosis of AI conditions is incomplete knowledge of the genes and mutations that can cause isolated and syndromic forms of AI. This barrier is addressed in SA1: to recruit and characterize AI families to determine their genetic etiology, identify new causative genes and mutations, and facilitate genetic testing. Once an AI proband is identified, a pedigree is constructed, and mode of inheritance assessed. Medical and dental histories are reviewed and dental records obtained. If a non-dental phenotype is ascertained, a medical consultation is coordinated with the physician. Subject DNA is characterized by whole-exome sequence (WES) analyses. WES analyses cover about 85% of all disease-causing mutations. Advances made in SA1 will increase knowledge of the genes and mutations that cause AI, enhance clinical genetic counseling, and result in practical advancements in gene-based testing, diagnosis, and intervention to improve patient prognoses. Until recently the greatest barrier to understanding the molecular mechanisms of dental enamel formation was a lack of knowledge of the critical molecular participants. Genetics has identified many new critical genes/proteins, so now the greatest barrier is understanding their functions. This barrier is addressed in SA2: to generate and characterize mouse models with defects homologous to human mutations to validate genetic discoveries, and define normal and disease mechanisms. Specific hypotheses are tested in wild-type and genetically modified mice concerning the normal function and pathological consequences of a loss of function of four genes critical for dental enamel formation: odontogenesis associated phosphoprotein (Odaph), acid phosphatase 4 (Acp4), RELT tumor necrosis factor receptor (Relt), and integrin beta 6 (Itgb6). OdaphC41*/C41* mice show a specific failure of post-secretory transition (PST) of ameloblasts into maturation, offering unique opportunities to understand the molecular mechanisms of PST. ACP4 is distinguished as either a lysosomal or secreted protein. The ligand that binds the RELT receptor is identified. The role of ITGß6 in matrix-cell interactions governing regulation of amelogenin expression is determined. The long term objective is to improve the diagnosis and management of AI conditions and to eventually to cure them.