bromochloroacetic-acid and Dental-Caries

Tooth enamel is the hardest substance in the human body and has a unique combination of hardness and fracture toughness that protects teeth from dental caries, the most common chronic disease worldwide. In addition to a high mineral content, tooth enamel comprises organic material that is important for mechanical performance and influences the initiation and progression of caries; however, the protein composition of tooth enamel has not been fully characterized. Here, we determined that epithelial hair keratins, which are crucial for maintaining the integrity of the sheaths that support the hair shaft, are expressed in the enamel organ and are essential organic components of mature enamel. Using genetic and intraoral examination data from 386 children and 706 adults, we found that individuals harboring known hair disorder-associated polymorphisms in the gene encoding keratin 75 (KRT75), KRT75(A161T) and KRT75(E337K), are prone to increased dental caries. Analysis of teeth from individuals carrying the KRT75(A161T) variant revealed an altered enamel structure and a marked reduction of enamel hardness, suggesting that a functional keratin network is required for the mechanical stability of tooth enamel. Taken together, our results identify a genetic locus that influences enamel structure and establish a connection between hair disorders and susceptibility to dental caries.

Topics: Adolescent; Adult; Amino Acid Substitution; Child; Child, Preschool; Dental Caries; Dental Enamel; Female; Hardness; Humans; Keratins; Male; Mutation, Missense

Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and sweat gland. RNA-seq analysis revealed that all PC-associated keratins (except for Krt6c that does exist in the mouse genome) are expressed in the mouse enamel organ. We further demonstrated that these keratins are produced by ameloblasts and are incorporated into mature human enamel. Using genetic and intraoral examination data from 573 adults and 449 children, we identified several missense polymorphisms in KRT6A, KRT6B and KRT6C that lead to a higher risk for dental caries. Structural analysis of teeth from a PC patient carrying a p.Asn171Lys substitution in keratin-6a (K6a) revealed disruption of enamel rod sheaths resulting in altered rod shape and distribution. Finally, this PC-associated substitution as well as more frequent caries-associated SNPs, found in two of the KRT6 genes, that result in p.Ser143Asn substitution (rs28538343 in KRT6B and rs151117600 in KRT6C), alter the assembly of K6 filaments in ameloblast-like cells. These results identify a new set of keratins involved in tooth enamel formation, distinguish novel susceptibility loci for tooth decay and reveal additional clinical features of pachyonychia congenita.

Topics: Adult; Amino Acid Substitution; Animals; Cells, Cultured; Child; Dental Caries; Dental Enamel; Female; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Keratin-6; Keratins; Male; Mice; Middle Aged; Pachyonychia Congenita; Polymorphism, Single Nucleotide; Rats; Tooth Erosion

Topics: Ameloblasts; Animals; Apatites; Calcium Phosphates; Cattle; Chemical Phenomena; Chemistry; Dental Bonding; Dental Caries; Dental Caries Susceptibility; Dental Enamel; Dental Enamel Proteins; Dental Enamel Solubility; Fluorides; Fluorosis, Dental; Hardness Tests; Humans; Keratins; Phosphoric Acids; Pit and Fissure Sealants; Surface Properties; Tooth Calcification