Tooth Development: Learn from ;;The Normal;; and ;;The Abnormal;;.

Tooth Development;Tooth Agenesis;Amelogenesis Imperfecta;FAM83H;Dental Enamel;Protein-protein Interaction;Dentistry;Health Sciences;Oral Health Sciences

Wang, Shih-KaiKrebsbach, Paul ;

University of Michigan

关键词: Tooth Development;    Tooth Agenesis;    Amelogenesis Imperfecta;    FAM83H;    Dental Enamel;    Protein-protein Interaction;    Dentistry;    Health Sciences;    Oral Health Sciences;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/107122/shihkaiw_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

For the past decades, tooth development has been extensively studied as a model for understanding organogenesis of ectoderm-derived structures. Much has been learned from the morphological patterning and molecular signaling of normal tooth development in model organisms, mainly rodents. On the other hand, human inherited dental anomalies also provide a valuable source for studying tooth development. Discerning the genetic etiology of these developmental defects not only enhances our understanding of normal tooth development but also provides a fundamental basis for developing potential therapeutic strategies for these disorders.Familial tooth agenesis (FTA) and amelogenesis imperfecta (AI) are the two most prevalent inherited dental defects in humans, characterized by failed tooth development and dental enamel malformations respectively. In this dissertation research, we described 7 FTA and 12 AI families and aimed to define the genetic etiology of the diseases through mutational analyses. By using target gene approaches and whole exome analyses, we successfully identified the disease-causing mutations in 2 FTA families and in all the AI cases. The results not only expanded the mutation spectrum of known disease-associated genes but also established novel candidate genes, revealing critical players in tooth and enamel development.Nevertheless, although human genetic studies of inherited dental and enamel defects have revealed many genes associated with the diseases, the functions of many of these genes and their roles in normal development and pathological conditions remain to be elucidated. Recently, mutations in FAM83H (family with sequence similarity 83, member H) were identified to cause autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI). Although many disease-causing FAM83H mutations have been reported, the cellular functions of this gene and the pathogenesis of its associated enamel defects are completely unknown. In this study, we used a biochemical approach to study FAM83H protein-protein interactions and identified CK1 (casein kinase 1) and SEC16A as FAM83H interacting proteins, which indicated a potential cellular function of FAM83H in vesicle trafficking and protein transport. The results also provided an explanation for the high mutation homogeneity of FAM83H disease-causing mutations revealed by human genetic studies and suggested a potential pathological mechanism for FAM83H-associated enamel defects.