Aggressive periodontitis is a rare disease characterized by rapid and severe periodontal tissue destruction, typically developing during the teens to twenties. Because it often leads to early tooth loss, it markedly impairs patient quality of life. Although familial clustering has suggested a genetic contribution, the causative gene has remained unknown. The aim of this study was to clarify the molecular basis of aggressive periodontitis through genetic and functional analyses. We identified a family with aggressive periodontitis showing an autosomal dominant inheritance pattern among patients treated at Hiroshima University Hospital. Whole-exome sequencing of affected family members revealed a heterozygous missense variant in MMD2 as a candidate pathogenic mutation. MMD2 was highly expressed in neutrophils, and patient-derived neutrophils showed significantly impaired chemotaxis toward bacterial stimuli compared with those from healthy controls. Proteomic analysis further demonstrated marked alterations in the protein expression profile of patient neutrophils, suggesting an underlying molecular basis for neutrophil dysfunction. To investigate the pathogenic significance of this variant in vivo, we generated knock-in mice carrying the corresponding Mmd2 mutation and established an experimental periodontitis model. Mutant mice exhibited significantly greater alveolar bone loss than wild-type mice. In addition, neutrophil infiltration into periodontal tissues was markedly reduced in the mutant mice, accompanied by persistent bacterial colonization. These findings suggest that MMD2 mutations contribute to the pathogenesis of aggressive periodontitis by impairing neutrophil function, thereby increasing susceptibility to infection and promoting destructive inflammation in periodontal tissues. This study is the first to identify MMD2 as a potential causative gene for aggressive periodontitis and to provide insight into its underlying molecular mechanism. Our findings may contribute to future genetic risk assessment, early intervention, and the development of personalized therapeutic strategies.
