A mutation in the ORAI1 gene studied in a human patient and mouse leads to calcium loss in enamel cells and results in defective dental enamel clearance, a study led by researchers at the NYU College of Dentistry finds.
The study published April 23 in Science Signaling identifies ORAI1 as the predominant protein for calcium influx and reveals the mechanisms by which calcium flow affects enamel cell function and tooth enamel formation.
Calcium is critical to many cellular functions, including mineralization of teeth and bones. Calcium enters cells via ORAI proteins that form pores in a cellular plasma membrane to allow calcium influx when activated.
"Our previous research has shown that deficiencies in calcium influx or calcium transport modulation result in malformation of the dental enamel," said Rodrigo Lacruz, Ph.D., associate professor of science and craniofacial biology at the NYU College of Dentistry and the study's senior author. "Despite this knowledge, the biology of enamel cells as it pertains to calcium signaling remains poorly understood."
Studies show that several genes, including ORAI (encoding ORAI proteins), are involved in the formation of tooth enamel. Enamel – the hard outer layer of teeth – first forms as a soft-like matrix. ORAI proteins then help the enamel-forming cells to mineralize.
Mutations in the human ORAI1 gene result in immune dysfunction and immune defense, but humans with ORAI1 mutations also have defects in their tooth enamel. In this study, the researchers examined cases of a patient with a complex medical history, including combined immunodeficiency and a mutation in the ORAI1 gene. Throughout his childhood, the patient had defects in his tooth enamel, resulting in severe cavities and related dental procedures. Based on his clinical presentation, the researchers concluded that the ORAI1 mutation probably accounted for the defective noble mineralization.
Due to the lack of dental samples from patients with ORAI1 mutations, Lacruz and his colleagues then developed mouse models to study ORAI's role of proteins in enamel formation, both by observing tooth enamel and examining its impact on the environment in enamel cells.
The researchers studied the ORAI family of proteins (ORAI1, ORAI2 and ORAI3) and genetic mutations in the corresponding genes to investigate mechanism by which calcium is modulated by each of these proteins. Since mice had a mutation in the ORAI1 gene and were therefore deficient in ORAI1 protein, calcium entry in enamel cells was significantly reduced (by about 50 percent) and the tooth enamel was abnormal, including cracks in the outer enamel layer. In contrast, mice with ORAI2 mutations and ORAI2 deficiency showed an increase in calcium by about 10%. 30 percent in the enamel cells, which did not result in obvious enamel faults. This suggests that ORAI1 is the dominant channel to modulate the influx of calcium into enamel cells.
To better understand how calcium influx and reverse calcium deficiency alter the function of enamel cells, the researchers examined the activity of cells lacking ORAI1. They found that calcium dysregulation in ORAI1 deficient cells affects their function at several levels, including increased mitochondrial respiration and subsequent changes in the redox balance. An increase in reactive oxygen species can be detrimental to the cells, and to protect proteins in an more intracellular environment that is more oxidizing, a mechanism called S-glutathionylation is promoted.
The results provide a basic understanding of what is happening in enamel cells, which can help create a pathway for researchers interested in regenerating tooth enamel or developing therapies for treating patients with enamel failure.
"We have long observed deficiencies in tooth enamel associated with abnormal calcium levels in the enamel cells, but can now detail a mechanism for how this happens," Lacruz said.
The cellular mechanism for transporting calcium in the formation of dental enamel cells
"Differential regulation of Ca2 + influx at ORAI channels mediates enamel mineralization," Science Signaling (2019). stke.sciencemag.org/lookup/doi … 26 / scisignal.aav4663
Calcium deficiency in cells due to ORAI1 gene mutation leads to damaged tooth enamel (2019, April 23)
April 24, 2019
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