Mutational spectrum of FAM83H gene in autosomal dominant hypocalcified AI

Objectives: To investigate for FAM83H gene (8q24.3) mutations in kindreds with autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI). Methods: Genomic DNA was isolated from peripheral whole blood. We amplified and sequenced all exons and exon/intron boundaries of the FAM83H gene. PCR products were purified and sequenced. To confirm the paternity in the spontaneous case, paternity test was performed using 15 genetic markers. Results: Nonsense mutations (c.1243G>T, p.E415X; c.891T>A, p.Y297X; c.1380G>A, p.W460X; and c.2029C>T, p.Q677X) were identified in the last exon (exon 5) of FAM83H in four families with ADHCAI. In three of the families the patterns of inheritance were autosomal dominant. The mutation in a family was spontaneous, as the mutation was present in the proband but absent in his biological parents, who had normal dentitions. The dental enamel in the affected members of our four AI kindreds is cheesy soft in consistency, light yellow in shade, and nearly normal in thickness until erupting into function. Thereafter the enamel layer is rapidly lost due to attrition. The abraded teeth lose contour, often becoming tapered toward the incisal edge or occlusal surface. The abraded surfaces are rough in texture, take up stain rapidly, and are sensitive to thermal changes. Most of the enamel crown is rapidly lost, but sporadic islands of enamel are retained for years and appear to be of near-normal hardness. Conclusions: The large C-terminal part of the protein (after 676 amino acids) is essential for proper enamel calcification, based on mutational spectrum of the FAM83H in the ADHCAI families. This work was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A060010), the Korea Science and Engineering Foundation (KOSEF) through the Biotechnology R&D program (#2006-05229), and NIDCR/NIH Grants DE015846 and DE011301.