Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay

Abstract

Background: Congenital forms of hearing impairment can be caused by mutations in the estrogen related receptor beta (ESRRB) gene. Our initial linkage studies suggested the ESRRB locus is linked to high caries experience in humans.

Methods: We tested for association between the ESRRB locus and dental caries in 1,731 subjects, if ESRRB was expressed in whole saliva, if ESRRB was associated with the microhardness of the dental enamel, and if ESRRB was expressed during enamel development of mice.

Results: Two families with recessive ESRRB mutations and DFNB35 hearing impairment showed more extensive dental destruction by caries. Expression levels of ESRRB in whole saliva samples showed differences depending on sex and dental caries experience.

Conclusions: The common etiology of dental caries and hearing impairment provides a venue to assist in the identification of individuals at risk to either condition and provides options for the development of new caries prevention strategies, if the associated ESRRB genetic variants are correlated with efficacy.

Figure 1

Flow chart of experiments included in this study. Experiments listed in order of appearance in manuscript and listed in the boxes. Results are listed in diamonds. Details of each experiment are provided in the Methods section.

Figure 2

Dental caries experience of families with hearing impairment DFNB35. Black indicates recessive hearing impairment. Dots indicate individuals who are heterozygous (carriers) for the mutation. Dental caries levels (high or low) and age in years are indicated below each subject assessed.

Figure 3

Enamel microhardness study design. Image above A depicts the five tooth surfaces upon which enamel microhardness was tested. Image above B is a close-up of the occlusal surface. Image above C shows the appearance of an enamel specimen ready to be tested. Image below D shows the testing unit. Microhardness was tested at baseline, after artificial caries creation, and after exposure to a fluoridated solution (panels above E, F, and G. are schematic representations of the assessments).

Figure 4

Summary of fine-mapping results. At the top, the fine-mapped region is highlighted on 14q24.3. Eight SNPs within or flanking ESRRB were associated with high caries experience.

Figure 5

Odds ratios for over-representation of the T allele (rs1676303) in individuals with high dental caries. A. Meta-analysis with the five studied groups suggest an association between ESRRB rs1676303 and dental caries. B. When the two study groups with less dental caries are removed from analysis, the association between ESRRB rs1676303 and dental caries becomes stronger.