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Primary failure of eruption (PFE) is a rare oral disease with an incidence rate of 0.06%. It is characterized by abnormal eruption mechanisms that disrupt tooth eruption. The underlying pathogenic genetic variant and mechanism of PFE remain largely unknown. The purpose of this study was to explore the role of a novel transmembrane protein 119 (TMEM119) mutation in two PFE patients in a Chinese family. Information collection was performed on the family with a diagnosis of PFE, and blood samples from patients and healthy family members were extracted. Whole-exome sequencing was performed. Bioinformatics analysis revealed that a heterozygous variant in the TMEM119 gene (c.G143A, p.S48L) was a disease-associated mutation in this family. Recombinant pcDNA3.1 plasmid-containing wild-type and mutant TMEM119 expression cassettes were successfully constructed and transfected into MC3T3-E1 cells, respectively. The results of in vitro analysis suggested that the subcellular distribution of the TMEM119 protein was transferred from the cell cytoplasm to the nucleus, and the ability of cells to proliferate and migrate as well as glycolytic and mineralized capacities were reduced after mutation. Furthermore, rescue assays showed that activating transcription factor 4 (ATF4) overexpression rescued the attenuated glycolysis and mineralization ability of cells. Results of in vivo analysis demonstrated that TMEM119 was mainly expressed in the alveolar bone around the mouse molar germs, and the expression level increased with tooth eruption, demonstrated using immunohistochemistry and immunofluorescence. Collectively, the novel TMEM119 mutation is potentially pathogenic in the PFE family by affecting the glucose metabolism and mineralized function of osteoblasts, including interaction with ATF4. Our findings broaden the gene mutation spectrum of PFE and further elucidate the pathogenic mechanism of PFE.
Xu et al. (Thu,) studied this question.